Amino-functional chalcones

ABSTRACT

The invention provides novel amino-functionalised chalcone derivatives and analogues thereof. Use of the compounds, or compositions comprising them, as pharmaceutically active agents, in particular against bacterial and parasitic infections, is also disclosed. The invention further relates to a method for detecting inhibitory effects against e.g., bacteria, parasites, fungi, and helminths. The chalcones of the invention carry amino substituents and exhibit enhanced biological effects combined with improved metabolic and physicochemical properties, making the compounds useful as drug substances, in particular as antiparasitic, and bacteriocidal agents.

FIELD OF THE INVENTION

The present Invention relates to a novel class of chalcone derivativesand analogues thereto as well as to use of a class of chalconederivatives as pharmaceutically active agents, In particular againstbacterial and parasitic infections.

Furthermore, the Invention relates to a method of predicting whether achemical compound has a potential inhibitory effect against an organismsuch as Helicobacter pylori and Plasmodium falciparum. The prediction isbased on the ability of the chemical compound to act as an inhibitior ofthe enzyme dihydroorotate dehydrogenase which is involved in thesynthesis of pyrimidine in prokaryotic as well as eukaryotic cells suchas bacteria, parasites, fungi, helminths and any type of mammalian cellssuch as human cells.

BACKGROUND OF THE INVENTION

Chalcones, e.g., for use against parasitic infections are known fromearlier patent applications assigned to the applicant, e.g. WO 93/17671and WO 99/00114. Moderate antibacterial activity has been reported for alimited number of chalcones in earlier publications e.g. Haraguchi, H.et al Phytochemistry 1998, 48, 125-129 and Hatano, T. et al Chem. Pharm.Bull (Tokyo) 2000, 48, 1286-92.

The bioavailability of several of the known chalcones is low due to thelow solubility of the compounds. The compounds do not typically dissolvein the intestine and are therefore not available for absorption.

The spread of antimicrobial resistance determinants particular amongnosocomial bacterial pathogens is an increasing problem. Such resistantpathogens Include Staphylococcus aureus resistant to methicillin andthus to all β-lactam-antibiotics and Enterococci resistant to vancomycin(VRE). Such resistant bacteria pose a significant therapeutic challengeand bacterial strains resistant to all currently availableantimicrobials are emerging. Furthermore, bacterial speciesintrinsically resistant to commonly employed antimicrobials are beingrecognized as important opportunistic pathogens in the setting oflong-term immunocompromized patients. An example of this isStenotrophomonas maltophilia which possesses a β-lactamase rendering thebacteria intrinsically resistant to carbapenems. As cross-resistancewithin a given class of antibiotics often occurs the development of newclasses of antibiotics is a neccisity to counter the emerging threat ofbacterial resistance.

The resistance of Plasmodium falciparum to chloroquine and otherantimalarial drugs have created an urgent need for new drugs that aresafe and effffective for the prophylaxis and treatment of malaria.

Furthermore, the Increasing appearance of resistance to first lineantileishmanial drugs, e.g. Pentostam or Glucantime, emphasizes the needfor new drugs for the treatment of Leishmania infections.

Thus, there is a need for chalcone derivatives with Improved therapeuticor prophylactic activity against parasites and bacteria.

Chalcones carrying certain amino substituents are known from Dimmock etal (I. Med. Chem. 1998, 41, 1014-26) and Cain et al (U.S. Pat. No.5,523,302).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Illustrates the general synthetic scheme for the preparation ofamino-functional chalcones where the aromatic rings are phenyl rings.R¹, R², and Z are as defined herein.

FIG. 2 illustrates the synthesis of amino-dihydrochalcones. R¹, R², andZ are as defined herein.

FIG. 3 illustrates a time-kill curve of A031 against S. aureusATCC29213. Bacterial growth is inhibited at concentrations at or abovethe MIC (MIC=9.4 μM). As CFU counts per ml decreases at concentrationsof compound above the MIC, the compound is bactericidal. The reductionin CFU/ml is faster as the concentration of test compound increasesabove the MIC. This indicates that the bactericidal action of thecompound is primarily dependent on the concentration of the testcompound.

FIG. 4 Illustrates a time-kill curve of A019 against S. aureusATCC29213. Bacterial growth is inhibited at concentrations of testcompound at or above the MIC (MIC=9.4 μM). As CFU counts per mldecreases at concentrations of compound above the MIC, the compound isbactericidal. The rate of reduction of CFU/ml is not significantlyaffected by increasing concentrations of test compound. Thus, thebactericidal action of the compound is primarily dependent on incubationtime.

FIG. 5 illustrates a dose-response curve of Licochalcone A (LicA) andone of the novel amino-chalcones (A139) at Plasmodium falciparum. Asshown at the figure, A139 is 18 times more potent than LicA.

FIG. 6 illustrates a dose-response curve of LicA and one of the novelamino-chalcones A037 at Leishmania Major. As shown at the figure, A037is 46 times more potent than LicA.

FIG. 7 illustrates an effect curve of A027 in Plasmodium berghei K173infected NMRI female mice following multiple intra venousadministrations. As shown at the figure, treatment with A027 causes asignificant decrease in the parasitaemia.

FIG. 8 illustrates an effect curve of A027 in Plasmodium berghei K173infected NMRI female mice following multiple oral administrations. Asshown at the figure, treatment with 027 causes a significant decrease inthe parasitaemia.

DESCRIPTION OF THE INVENTION

The present inventors have found that the amino-functional chalconesdefined herein exhibit interesting biological properties combined withimproved metabolic and physicochemical properties which make thecompound useful as drug substances, in particular as antiparasiticagents, bacterlostatic agents, and bacterlocidal agents.

It is believed that the amino group or groups of the amino-functionalchalcone will be charged according to pH of the medium and the pKa ofthe compound. The solubility of the charged compounds is significantlyhigher than the solubility of the neutral compounds. As theamino-functional chalcones will be partially charged and thus soluble inaqueous solutions at physiological pH values in the intestine orstomach, they will dissolve in the gastric juices and then be availablefor absorption. The bioavailability of the amino-functional chalconeswill therefore be improved compared to the known neutral chalcones, thusmaking the compounds generally useful as drug candidates. Also, thepresent amino-functional chalcones possess different pKa values whichallows the selection of a chalcone derivative with optimalcharged/non-charged ratio at a given pH value.

Furthermore, the application of the known chalcones as drug candidateshave been limited due to extensive metabolism of the compounds, whichresults in short half-lives in vivo. The present inventors have nowfound that introduction of an amino group in the chalcone moleculeaffects the metabolic properties so as to achieve improved metabolicstability.

The introduction of an alifatic amino-group and hence a positive charge(at the pH value of the target site) affects the mode of interactionwith the biological target. It is anticipated that the compoundsinteract with the target in a different way than neutral chalcones, dueto the possibility of strong electrostatic interactions (attraction aswell as repulsion). This is indeed reflected in the activity of thecompounds, being more potent than the previously described neutralchalcones.

Of particular interest, the present inventors have found that theamino-functional chalcones defined herein are far more potent againstmalaria and leishmania parasites than the earlier described neutralchalcone compounds, and that they exhibit excellent bacteriocidal andbacteriostatic properties, even against multi-resistant bacteriastrains.

Thus, in a first aspect, the present invention provides chalconederivatives and analogues of the general formula:(Y¹)_(m)—Ar¹(X¹)—C(═O)VAr²(X²)—(Y²)_(p)

wherein Ar¹ and Ar2 independently may be selected from aryl orheteroaryl;

V designates —CH₂—CH₂—, —CH═CH— or —C≡C—, preferably —CH═CH—;

m is 0, 1, or 2,

p is 0, 1, or 2,

wherein the sum of m and p is at least 1;

each Y¹ is independently selected from an amino-functional substituentof the formula-Z-N(R¹)R²,

each Y² is independently selected from an amino-functional substituentof the formula-Z-N(R¹)R²,

wherein Z is a biradical —(C(R^(H))₂)_(n)—, wherein n is an integer inthe range of 1-6, preferably 1-4, such as 1-3, and each R^(H) isindependently selected from hydrogen or C₁₋₆-alkyl, or two R^(H) on thesame carbon atom may designate ═O;

R¹ and R² independently may be selected from hydrogen, optionallysubstituted C₁₋₁₂-alkyl, optionally substituted C₂₋₁₂-alkenyl,optionally substituted C₄₋₁₂-alkadienyl, optionally substitutedC₆₋₁₂-alkatrienyl, optionally substituted C₂₋₁₂-alkynyl, optionallysubstituted C₁₋₁₂-alkoxycarbonyl, optionally substitutedC₁₋₁₂-alkylcarbonyl, optionally substituted aryl, optionally substitutedaryloxycarbonyl, optionally substituted arylcarbonyl, optionallysubstituted heteroaryl, optionally substituted heteroaryloxycarbonyl,optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, or mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,

or R¹ and R² together with the nitrogen atom to which they are attached(—N(R¹)R²) form an optionally substituted nitrogen-containingheterocyclic ring; X¹ and X² independently may designate 0-5, preferably0-4, such as 0-3, e.g. 0-2, substituents, where such optionalsubstituents independently may be selected from optionally substitutedC₁₋₁₂-alkyl, optionally substituted C₂₋₁₂-alkenyl, optionallysubstituted C₄₋₁₂-alkadienyl, optionally substituted C₆₋₁₂-alkatrienyl,optionally substituted C₂₋₁₂-alkynyl, hydroxy, optionally substitutedC₁₋₁₂-alkoxy, optionally substituted C₂₋₁₂-alkenyloxy, carboxy,optionally substituted C₁₋₁₂-alkoxycarbonyl, optionally substitutedC₁₋₁₂-alkylcarbonyl, formyl, C₁₋₆-alkylsulphonylamino, optionallysubstituted aryl, optionally substituted aryloxycarbonyl, optionallysubstituted aryloxy, optionally substituted arylcarbonyl, optionallysubstituted arylamino, arylsulphonylamino, optionally substitutedheteroaryl, optionally substituted heteroaryloxycarbonyl, optionallysubstituted heteroaryloxy, optionally substituted heteroarylcarbonyl,optionally substituted heteroarylamino, optionally substituted(heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionallysubstituted heterocyclyl, optionally substitutedheterocyclyloxycarbonyl, optionally substituted heterocyclyloxy,optionally substituted heterocyclylcarbonyl, optionally substitutedheterocyclylamino, heterocyclylsulphonylamino, amino, mono- anddi(C₁₋₆-alkyl)amino, carbatnoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,amino-C₁₋₆-alkyl-carbonylamino, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-carbonylamino, cyano, guanidino,carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,C₁₋₆-alkylsulphonyl-oxy, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, or halogen, where any nitrogen-bound C₁₋₆-alkyl may besubstituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino, halogen,C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidine;

and salts thereof.

The substituents R¹ and R² carried by the nitrogen atom of the aminosubstituent are believed to slightly alter the pKa value of the chalconederivative. Thus, the particular selection of the groups R¹ and R² maybe used to “fine-tune” the pKa value in view of the particular conditionor disease and the intended route of administration.

In one embodiment, R¹ and R² may be independently selected fromhydrogen, optionally substituted C₁₋₁₂-alkyl, optionally substitutedC₂₋₁₂-alkenyl, optionally substituted C₂₋₁₂-alkynyl, optionallysubstituted C₁₋₁₂-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,amino-carbonyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, and mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl. In particular R¹ and R²are independently selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkylcarbonyl,heteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, or mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl.

In another embodiment, R¹ and R² together with the nitrogen atom towhich they are attached (—N(R¹)R²) form an optionally substitutednitrogen-containing heterocyclic ring.

In still a further embodiment, X¹ and X² independently may designate0-4, such as 0-3, e.g. 0-2, substituents, where such optionalsubstituents independently may be selected from optionally substitutedC₁₋₁₂-alkyl, hydroxy, optionally substituted C₁₋₁₂-alkoxy, optionallysubstituted C₂₋₁₂-alkenyloxy, carboxy, optionally substitutedC₁₋₁₂-alkylcarbonyl, formyl, C₁₋₆-alkylsulphonylamino, optionallysubstituted aryl, optionally substituted aryloxycarbonyl, optionallysubstituted aryloxy, optionally substituted arylcarbonyl, optionallysubstituted arylamino, arylsulphonylamino, optionally substitutedheteroaryl, optionally substituted heteroarylamino, optionallysubstituted (heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, optionally substituted heteroarylcarbonyl,optionally substituted heteroaryloxy, heteroarylsulphonylamino,optionally substituted heterocyclyl, optionally substitutedheterocyclyloxy, optionally substituted heterocyclylamino, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,amino-C₁₋₆-alkyl-carbonylamino, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-carbonylamino, guanidino, carbamido,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, C₁₋₆-alkylsulphonyloxy,optionally substituted C₁₋₆-alkylthio, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, and halogen, where any nitrogen-boundC₁₋₆-alkyl may be substituted with hydroxy, C₁₋₆-alkoxy, and/or halogen,in particular X¹ and X² independently designates 0-3, e.g. 0-2,substituents, where such optional substituents independently areselected from optionally substituted C₁₋₆-alkyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy, carboxy, optionally substitutedC₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulphonylamino, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylamino,arylsulphonylamino, optionally substituted heteroaryl, optionallysubstituted heteroarylamino, optionally substituted(heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, amino, mono- anddi(C₁₋₆-alkyl)amino, carbamoyl, C₁₋₆-alkyl-carbonylamino, guanidino,carbamido, optionally substituted C₁₋₆-alkylthio, optionally substitutedheterocyclyl, optionally substituted heterocyclyloxy, optionallysubstituted heterocyclylamino and halogen, where any nitrogen-boundC₁₋₆-alkyl may be substituted with hydroxy, C₁₋₆-alkoxy, and/or halogen.

In a suitable embodiment, X¹ and X² independently designates 0-5,preferably 0-4, such as 0-3, e.g. 0-2, substituents, where such optionalsubstituents independently are selected from optionally substitutedC₁₋₁₂-alkyl, optionally substituted C₂₋₁₂-alkenyl, optionallysubstituted C₄₋₁₂-alkadienyl, optionally substituted C₆₋₁₂-alkatrienyl,optionally substituted C₂₋₁₂-alkynyl, hydroxy, optionally substitutedC₁₋₁₂-alkoxy, optionally substituted C₂₋₁₂-alkenyloxy, carboxy,optionally substituted C₁₋₁₂-alkoxycarbonyl, optionally substitutedC₁₋₁₂alkylcarbonyl, formyl, C₁₋₆-alkylsulphonylamino, optionallysubstituted aryl, optionally substituted aryloxycarbonyl, optionallysubstituted aryloxy, optionally substituted arylcarbonyl, optionallysubstituted arylamino, arylsulphonylamino, optionally substitutedheteroaryl, optionally substituted heteroaryloxycarbonyl, optionallysubstituted heteroaryloxy, optionally substituted heteroarylcarbonyl,optionally substituted heteroarylamino, optionally substituted(heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionallysubstituted heterocyclyloxycarbonyl, optionally substitutedheterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionallysubstituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino ,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, C₁ 6-alkylsulphonyl-oxy, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, and halogen, where any nitrogen-bound C₁₋₆-alkyl may besubstituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, carboxy,halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

In a particular embodiment, X¹ and X² independently may designate 0-3,e.g. 0-2, substituents, where such optional substituents mayindependently be selected from optionally substituted C₁₋₆-alkyl,hydroxy, optionally substituted C₁₋₆-alkoxy, carboxy, optionallysubstituted C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulphonylamino, optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedarylamino, amino, mono- and di(C₁₋₆-alkyl)amino, arylsulphonylamino,optionally substituted heteroaryl, optionally substitutedheteroarylamino, optionally substituted (heteroarylalkyl)amino,optionally substituted (heteroarylalkyl)alkylamino,heteroarylsulphonylamino, carbamoyl, C₁₋₆-alkyl-carbonylamino,guanidino, carbamido, optionally substituted C₁₋₆-alkylthio, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen, where any nitrogen-bound C₁₋₆-alkyl may be substituted withat least one substituent selected from the group consisting of hydroxy,C₁₋₆-alkoxy, or halogen.

The group V is relevant with respect to the spatial orientation of therings Ar¹ and Ar². Thus, the group V may be —CH₂—CH₂—, —CH═CH— or —C≡C—in a currently interesting embodiment thereof, V designates —CH═CH—.

In the context of the present invention, the expression “chalconederivative” is to be assigned to the compounds of the above formula inthat the overall structure namely Ar¹—C(═O)—C—C—Ar² resembles that ofthe chalcone structure. This being said, Ar¹ and Ar² are selected fromaromatic rings and heteroaromatic rings. It is currently believed thatparticularly interesting compounds are those where at least one of Ar¹and Ar^(2,) preferably both, are aryl, in particular phenyl. This beingsaid, the inventors envisage that the functionality of the compounds maybe substantially preserved (or even improved) when one or both of Ar¹and Ar² are heteroaromatic rings.

In one embodiment, at least one of Ar¹ and Ar² is selected fromthiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, thienyl, quinolyl, isoquinolyl, and indolyl.

In another embodiment, both of Ar¹ and Ar² are phenyl rings and Y¹represent at least one amino-functional substituent, i. e. m is 1 or 2,and p is 0.

In a further embodiment, X² represents at least one substituent selectedfrom C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylcarbonyl, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylamino,optionally substituted heteroaryl, optionally substitutedheteroarylamino, optionally substituted (heteroarylalkyl)amino,optionally substituted (heteroarylalkyl)alkylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen.

In a yet further embodiment, X² represents at least one substituentselected from C₁-alkyl, C₁₋₆-alkoxy, optionally substituted aryl,optionally substituted aryloxy, optionally substituted arylamino,optionally substituted heteroaryl, optionally substitutedheteroarylamino, optionally substituted (heteroarylalkyl)amino,optionally substituted (heteroarylalkyl)alkylamino, mono- anddi(C₁₋₆-alkyl)amino, optionally substituted heterocyclyl and halogen.

The Z group represents the biradical between the ring and the aminofunctionality. This group Z is typically a biradical —(C(R^(H))₂)_(n)—,wherein n is an integer in the range of 1-6, preferably 1-4, such as1-3, where each R^(H) is independently selected from hydrogen andC₁₋₆-alkyl, or two R^(H) on the same carbon atom may designate ═O. Aparticular example of Z is —(CH₂)_(n)— wherein n is 1-4, such as 1-3.

Thus, in a particular embodiment, one of Y¹ and Y² represent asubstituent of the formula—CH₂—N(R¹)R²

wherein R¹ and R² is selected from hydrogen and C₁₋₆-alkyl. Furthermore,V is preferably —CH═CH—, and Ar¹ and Ar² both are phenyl rings. In aparticular embodiment, Y¹ represents the substituent for the formula—CH₂—N(R¹)R².

In one preferred embodiment, m is 1 and p is 0. in another preferredembodiment m is 0 and p is 1. in a further interesting embodiment, m andp are both 1.

In a further typical embodiment, where Ar¹ and Ar² are both phenyl, V is—CH═CH—, Z is CH₂, R¹ and R² are methyl or together form a morpholinogroup, and one of m and p is 2 while the other of m and p is 0,

X¹ and X² independently may designate 0-5, preferably 0-4, such as 0-3,e.g. 0-2, substituents, where such optional substituents mayindependently be selected from optionally substituted C₁₋₁₂-alkyl,optionally substituted C₂₋₁₂-alkenyl, optionally substitutedC₄₋₁₂-alkadienyl, optionally substituted C₆₋₁₂-alkatrienyl, optionallysubstituted C₂₋₁₂-alkynyl, 2-, 3-, 5-, or 6-hydroxy, optionallysubstituted C₁₋₁₂-alkoxy, optionally substituted C₂₋₁₂-alkenyloxy,carboxy, optionally substituted C₁₋₁₂-alkoxycarbonyl, optionallysubstituted C₁₋₁₂-alkylcarbonyl, formyl, C₁₋₆-alkylsulphonylamino,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted aryloxy, optionally substituted arylcarbonyl,optionally substituted arylamino, arylsulphonylamino, optionallysubstituted heteroaryl, optionally substituted heteroaryloxycarbonyl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, optionally substituted heteroarylamino, optionallysubstituted (heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionallysubstituted heterocyclyloxycarbonyl, optionally substitutedheterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionallysubstituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino ,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, C₁₋₆-alkylsulphonyl-oxy, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, or halogen, where any nitrogen-bound C₁₋₆-alkyl may besubstituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, carboxy,halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidine;

provided that

when Ar¹ and Ar² are both phenyl, V is —CH═CH—, m is 1, p is 0, Y1 is2—CH₂NMe2, and X2 is absent, then X1 is not solely 4-methoxy;

when Ar¹ and Ar² are both phenyl, V is —CH═CH—, m is 1, p is 0, Y1 is 3-or 4—CH2NR1R2, wherein R1 and R2 are selected from hydrogen, methyl, andethyl, and X1 is solely 4-hydroxy or 4-alkoxy, or absent, then X2 is notsolely nitro, dichloro, carboxymethoxy, methoxycarbonylmethoxy,ethoxycarbonylmethoxy, 2-carboxyethyl, or absent;

when Ar¹ and Ar² are both phenyl, V is —CH═CH—, m is 0, p is 1, Y² issolely 2- or 3-CH₂NR¹R², wherein R¹ and R² are selected from hydrogen,methyl, and ethyl, and X² is solely 4-OH, or absent, then X¹ is notsolely ethoxycarbonylmethoxy, dichloro, or absent.

Generally preferred compounds may, e.g., be selected from the groupcomprising:

-   1-(4-Methoxy-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-propenone,-   3-(4-Diethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-(4-propylaminomethyl-phenyl)-propenone,-   3-(4-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,-   3-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-(4-piperidin-1-ylmethyl-phenyl)-propenone,-   3-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,-   3-(4-Dibutylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,-   3-{4-[(4-Diethylamino-1-methyl-butylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,-   3-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-(3-propylaminomethyl-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-(4-Methoxy-phenyl)-3-[3-(4-methyl-[1,4]diazepan-1-ylmethyl)-phenyl]-propenone,-   3-(3-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,-   1-(2-Bromo-phenyl)-3-(2-dimethylaminomethyl-phenyl)-propenone,-   3-{3-[(3-Dimethylamino-propylamino)-methyl]-phenyl{-1-(4-methoxy-phenyl)-propenone-   3-(2,5-Dimethoxy-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,-   3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-{3-[(3-dimethylamino-propylamino)-methyl]-phenyl}-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-{4-[(3-dimethylamino-propylamino)-methyl]-phenyl}-propenone,-   3-(3-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-(4-Dibutylamino-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(4-Dibutylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(4-Dibutylamino-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(3-Dimethylaminomethyl-phenyl)-1-pyridin-2-yl-propenone,-   3-(4-Dibutylamino-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,-   3-[5-(1,1-Dimethyl-allyl)-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl]-3-(2,4-dichloro-phenyl)-propenone,-   Acetic acid    1-{2-[3-(2,4-dichloro-phenyl)-acryloyl]-benzyl}-piperidin-4-yl    ester,-   3-(2,4-Dichloro-phenyl)-1-(2-morpholin-4-ylmethyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-propenone,-   3-(4-Diethylaminomethyl-phenyl)-1-o-tolyl-propenone,-   3-(3-Dimethylaminomethyl-phenyl)-1-(2-methoxy-phenyl)-propenone,-   3-(4-Chloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(2,4-Difluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(3-Butylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(4-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(2-diethylaminomethyl-phenyl)-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-(4-hydroxy-2-methoxy-5-propyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-fluoro-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-[2-(4-hydroxy-piperidin-1-ylmethyl)-phenyl]-propenone,-   1-(3-Diethylaminomethyl-phenyl)-3-(2,5-dimethoxy-phenyl)-propenone,-   3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2,4-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(4-Imidazol-1-yl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-2-yl-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-3-yl-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-4-yl-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1-methyl-1H-pyrrol-2-yl)-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1H-pyrrol-2-yl)-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-thiophen-2-yl-propenone,-   1,3-Bis-(2-diethylaminomethyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(3-diethylaminomethyl-phenyl)-propenone,-   3-(4-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(3-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(3-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(2-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[3-(Butyl-ethyl-amino)-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone,-   3-(2-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2-Diethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1,3-Bis-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(4-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(1H-Indol-5-yl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2,4-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-(4-imidazol-1-yl-phenyl)-propenone,-   1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-[3-(pyridin-3-ylamino)-phenyl]-propenone,-   3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-{3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-benzoic    acid,-   1-(2-Dimethylaminomethyl-phenyl)-3-(2,4-dimethyl-phenyl)-propenone,-   3-(2,4-Dimethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-(1-methyl-1H-pyrrol-2-yl)-propenone,-   3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-ethoxy-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(3-Dimethylaminomethyl-4-methoxy-phenyl)-1-(4-methoxy-phenyl)-propenone,-   1-(2-Methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-(2-Fluoro-4-methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-3-ylamino)-phenyl]-propenone,-   3-(2-Dimethylaminomethyl-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,-   1-(3-Dimethylaminomethyl-phenyl)-3-(3-morpholin-4-ylmethyl-phenyl)-propenone,-   1-(3-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   1-(3-Dimethylaminomethyl-phenyl)-3-(4-pyridin-2-yl-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-(3-{[methyl-(2-methylamino-ethyl)-amino]-methyl}-phenyl)-propenone,-   3-(2-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-(2-Dimethylaminomethyl-phenyl)-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-(3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-(3-methylaminomethyl-phenyl)-propenone,-   1-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone,-   3-{3-[(2-Methoxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[2-methoxy-5-(pyridin-3-ylamino)-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   1-(4-Methoxy-phenyl)-3-(3-piperazin-1-ylmethyl-phenyl)-propenone,-   3-(3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone,-   3-(3-{[(2-3-{3-[(2-Hydroxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,-   3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone,-   1-[4-(2-Dimethylamino-ethyl)-phenyl]-3-(4-methoxy-biphenyl-3-yl)-propenone,-   3-(4,2′-Dimethoxy-biphenyl-3-yl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone,-   3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   3-(3′,5′-Dichloro-4,6-dimethoxy-biphenyl-3-yl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-{3-[(pyridin-3-ylmethyl)-aminol-phenyl}-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propenone,-   1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propenone,-   3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-(5-tert-Butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,    or-   3-[5-(1,1-Dimethyl-ally)-4-hydroxy-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-phenyl)-propenone.

While the above-mentioned group of compounds is intended to include allstereoisomers, including optical isomers, and mixtures thereof, as wellas pure, partially enriched, or, where relevant, racemic forms, agenerally preferred embodiment of the above-mentioned compounds has theE-configuration at the enone functionality.

In a further aspect, the invention further provides combinatoriallibraries, mixtures and kits for screening compounds as defined above.

In one embodiment, a combinatorial library comprising at least twocompounds of the general formula is provided. Such library may be in theform of an equimolar mixture, or in a mixture of any stoichiometry.Typical embodiments comprise at least two, such as at least 10, such asat least 100, such as at least 1000, such as at least 10000, such as atleast 100000 compounds as defined above.

In another embodiment, combinatorial compound collections in the form ofkits for screening for biologically or pharmacologically activecompounds are provided. Such kits comprise at least two topologicallydistinct singular compounds of the general formula defined above.Typical kits comprise at least 10, such as at least 100, such as atleast 1000, such as at least 10000, such as at least 100000 compounds asdefined above. Kits are preferably provided in the form of solutions ofthe compounds in appropriate solvents.

Further provided are methods for screening for pharmacologically activecompounds, especially bacteriostatic, bacteriocidal and antiparasiticagents, consisting of the steps of preparing a kit or library comprisingat least two compounds of the general formula defined above, contactingsaid kit or library with a target molecule, such as a protein or nucleicacid, a target tissue, or a target organism, such as a bacterium orparasite, and detecting a biological or pharmacological response causedby at least one compound. Optionally, the steps may be repeated asappropriate to achieve deconvolution.

DEFINITIONS

In the present context, the term “bacteriostatic” is intended todescribe an antimicrobial activity of a test compound, characterized byan inhibition of bacterial growth in the absence of a reduction ofviable bacteria (bacterial kill) during incubation with the testcompound, as evidenced in the killing curve determination by astationary number of colony forming units (CFU) during incubation time.

In the present context, the term “bacteriocidal” is intended to describean antimicrobial activity of a test compound, characterized by thereduction of viable bacteria (bacterial kill) during incubation with thetest compound, as evidenced in the killing curve determination by areduction of colony forming units (CFU) during incubation time.

In the present contest, the term “antiparasitic” is intended to describethe ability of a test compound to upon incubation in vitro with aculture of parasites, e.g. Leishmania major or Plasmodium falciparum, toinhibit metabolic labelling of the parasites by at least 50% compared tomock treated control cultures.

In the present context, the term “C₁₋₁₂-alkyl” is intended to mean alinear, cyclic or branched hydrocarbon group having 1 to 12 carbonatoms, such as methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl,tert-butyl, iso-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, etc. Analogously, the term “C₁₋₆-alkyl” is intended to meana linear, cyclic or branched hydrocarbon group having 1 to 6 carbonatoms, such as methyl, ethyl, propyl, iso-propyl, pentyl, cyclopentyl,hexyl, cyclohexyl, and the term “C₁₋₄-alkyl” is intended to coverlinear, cyclic or branched hydrocarbon groups having 1 to 4 carbonatoms, e.g. methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl,iso-butyl, tert-butyl, cyclobutyl.

Whenever the term “C₁₋₁₂-alkyl is used herein, it should be understoodthat a particularly interesting embodiment thereof is “C₁₋₆-alkyl”.

Similarly, the terms “C₂₋₁₂-alkenyl”, “C₄₋₁₂-alkadienyl”, and“C₆₋₁₂-alkatrienyl” are intended to cover linear, cyclic or branchedhydrocarbon groups having 2 to 12, 4 to 12, and 6 to 12, carbon atoms,respectively, and comprising one, two, and three unsaturated bonds,respectively. Examples of alkenyl groups are vinyl, allyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl. Examples ofalkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl,heptadecadienyl. Examples of alkatrienyl groups are hexatrienyl,heptatrienyl, octatrienyl, and heptadecatrienyl. Preferred examples ofalkenyl are vinyl, allyl, butenyl, especially allyl.

Similarly, the term “C₂₋₁₂-alkynyl” is intended to mean a linear orbranched hydrocarbon group having 2 to 12 carbon atoms and comprising atriple bond. Examples hereof are ethynyl, propynyl, butynyl, octynyl,and dodecaynyl.

Whenever the terms “C₂₋₁₂-alkenyl”, “C₄₋₁₂-alkadienyl”,“C₆₋₁₂-alkatrienyl”, and “C₂₋₁₂-alkynyl” are used herein, It should beunderstood that a particularly interesting embodiment thereof are thevariants having up to six carbon atoms.

In the present context, i.e. in connection with the terms “alkyl”,“alkenyl”, “alkadienyl”, “alkatrienyl”, and “alkynyl”, the term“optionally substituted” is intended to mean that the group in questionmay be substituted one or several times, preferably 1-3 times, withgroup(s) selected from hydroxy (which when bound to an unsaturatedcarbon atom may be present in the tautomeric keto form), C₁₋₆-alkoxy(i.e. C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming a keto oraldehyde functionality), C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxycarbonyl, aryloxy, arylamino, arylcarbonyl,heteroaryl, heteroarylamino, heteroaryloxycarbonyl, heteroaryloxy,heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino, carbamoyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkyl-carbonylamino, cyano, guanidino, carbamido,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkanoyloxy, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylsulphonyloxy, nitro, C₁₋₆-alkylthio,halogen, where any aryl and heteroaryl may be substituted asspecifically describe below for “optionally substituted aryl andheteroaryl”, and any alkyl, alkoxy, and the like representingsubstituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

Preferably, the substituents are selected from hydroxy (which when boundto an unsaturated carbon atom may be present in the tautomeric ketoform), C₁₋₆-alkoxy (i.e. C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo(forming a keto or aldehyde functionality), C₁₋₆-alkylcarbonyl, formyl,aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroarylamino,heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino;carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,guanidino, carbamido, C₁₋₆-alkyl-sulphonyl-amino, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkylsulphinyl, C₁₋₆-alkylthio, halogen, where any aryl andheteroaryl may be substituted as specifically describe below for“optionally substituted aryl and heteroaryl”.

Especially preferred examples are hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, and guanidine.

The terms “optionally substituted C₁₋₁₂-alkoxy” and “optionallysubstituted C₁₋₆-alkoxy” are intended to mean that the alkoxy groups maybe substituted one or several times, preferably 1-3 times, with group(s)selected from hydroxy (which when bound to an unsaturated carbon atommay be present in the tautomeric keto form), C₁₋₆-alkoxy (i.e.C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming a keto oraldehyde functionality), C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl,heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, carbamoyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, cyano,guanidino, carbamido, C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkanoyloxy, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylsulphonyloxy, nitro, C₁₋₆-alkylthio,halogen, where any aryl and heteroaryl may be substituted asspecifically describe below for “optionally substituted aryl andheteroaryl.

Especially preferred examples of “optionally substituted C₁₋₁₂-alkoxy”and “optionally substituted C₁₋₆-alkoxy” groups are unsubstituted suchgroups as well as those carrying one or two substituents selected fromhydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, carboxy, halogen, orC₁₋₆-alkylthio.

“Halogen” includes fluoro, chloro, bromo, and iodo.

In the present context the term “aryl” is intended to mean a fully orpartially aromatic carbocyclic ring or ring system, such as phenyl,naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl,benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferredexample.

The term “heteroaryl” is intended to mean a fully or partially aromaticcarbocyclic ring or ring system where one or more of the carbon atomshave been replaced with heteroatoms, e.g. nitrogen (═N— or —NH—),sulphur, and/or oxygen atoms. Examples of such heteroaryl groups areoxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl,benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl,tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl,benzopyrazolyl, phenoxazonyl. Particularly interesting heteroaryl groupsare oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl,thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl inparticular pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, thienyl,quinolyl, tetrazolyl, and isoquinolyl.

The term “heterocyclyl” is intended to mean a non-aromatic carbocyclicring or ring system where one or more of the carbon atoms have beenreplaced with heteroatoms, e.g. nitrogen (═N— or —NH—), sulphur, and/oroxygen atoms. Examples of such heterocyclyl groups are imidazolidine,piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane,diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine,azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine,dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane,oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane,oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran,oxepane, tetrahydrothlophene, tetrahydrothiopyrane, thiepane, dithiane,dithiepane, dioxane, dioxepane, oxathiane, oxathiepane. The mostinteresting examples are imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane,oxazepane, thiazolane, thiazinane, and thiazepane, in particularimidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine,diazepane, pyrrolidine, piperldine, azepane, oxazinane (morpholine), andthiazinane.

In the present context, when applied to groups of aromatic character,i.e. in connection with the terms “aryl”, “heteroaryl”, “heterocyclyl”,“heteroarylamino”, “(heteroarylalkyl)amino”,“(heteroarylalkyl)alkylamino”, etc, the term “optionally substituted” isintended to mean that the group in question may be substituted one orseveral times, preferably 1-5 times, in particular 1-3 times) withgroup(s) selected from hydroxy (which when present in an enol system maybe represented in the tautomeric keto form), C₁₋₆-alkyl, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, oxo (which may be represented in the tautomeric enolform), carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl, formyl, aryl,aryl-oxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl,heteroarylamino, amino, mono- and di(C₁₋₆-alkyl)amino; carbamoyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-sulphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulfonyl, mono-and di(C₁₋₆-alkyl)amino-sulfonyl, dihalogen-C₁₋₄-alkyl,trihalogen-C₁₋₄-alkyl, halogen, where aryl and heteroaryl representingsubstituents may be substituted 1-3 times with C₁₋₄-alkyl, C₁₋₄-alkoxy,nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the likerepresenting substituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

Preferably, the substituents are selected from hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, oxo (which may be represented in the tautomeric enol form),carboxy, C₁₋₆-alkylcarbonyl, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino; carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino, guanidino,carbamido, C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl, mono- anddi(C₁₋₆-alkyl)amino-sulfonyl or halogen, where any alkyl, alkoxy and thelike representing substituents may be substituted with hydroxy,C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine. Especially preferred examplesare C₁₋₆-alkyl, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the likerepresenting substituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbony-lamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine. lamino, in the present contextthe term “nitrogen-containing heterocyclic ring” is intended to meanheterocyclic ring or ring system in which at least one nitrogen atom ispresent. Such a nitrogen is, with reference to the formula, carrying thesubstituents R₁ and R₂. The “nitrogen-containing heterocyclic ring” mayfurther comprise additional heteroatoms, e.g. nitrogen (═N— or —N—),sulphur, and/or oxygen atoms. Examples of such rings are aromatic ringssuch as pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiophene,oxazole, isoxazole, thiazole, isothlazole, pyrrole, imidazole, pyrazole,tetrazole, quinoline, benzothiazole, benzotriazole, benzodiazole,benzoxozole, triazole, isoquinoline, indole, benzopyrazole, thiadiazole,and oxadiazole. The most interesting examples of aromatic rings arepyridine, pyridazine, pyrimidine, pyrazine, thiophene, tetrazole,oxazole, isoxazole, thiazole, isothiazole, pyrrole, imidazole, pyrazole,quinoline, triazole, isoquinoline, and indole, in particular pyridine,thiophene, imidazole, quinoline, isoqutnoline, indole, and tetrazole.

Other examples of such rings are non-aromatic rings such asimidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine,diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane,aziridine, azirine, azetidine, pyroline, tropane, oxazinane(morpholine), azepine, dihydroazepine, tetrahydroazepine, andhexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane,thiazinane, thiazepane, thiazocane, oxazetane, diazetane, andthiazetane. The most interesting examples of non-aromatic rings areimidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine,diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane,azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane,thiazolane, thiazinane, and thiazepane, in particular imidazolidine,piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane,pyrrolidine, piperidine, azepane, oxazinane (morpholine), andthiazinane.

In the present context, i.e. in connection with the term“nitrogen-containing heterocyclic ring”, the term “optionallysubstituted” is intended to mean that the group in question may besubstituted one or several times, preferably 1-5 times, in particular1-3 times) with group(s) selected from the same substituents as definedabove for “optionally substituted aryl”.

As is evident from the formulae defined herein and the definitionsassociated therewith, certain compounds of the present invention arechiral. Moreover, the presence of certain cyclic fragments or multiplestereogenic atoms provides for the existence of diastereomeric forms ofsome of the compounds. The invention is intended to include allstereoisomers, including optical isomers, and mixtures thereof, as wellas pure, partially enriched, or, where relevant, racemic forms.

Embodiments where V is —CH═CH— may comprise E- and Z-stereoisomers, ormixtures of such isomers, which may exist in a dynamic equilibrium issolution. The E-isomers are generally preferred.

It should furthermore be understood that the compounds defined hereininclude possible salts thereof, of which pharmaceutically acceptablesalts are of course especially relevant for the therapeuticapplications. Salts include acid addition salts and basic salts.Examples of acid addition salts are hydrochloride salts, fumarate,oxalate, etc. Examples of basic salts are salts where the (remaining)counter ion is selected from alkali metals, such as sodium andpotassium, alkaline earth metals, such as calcium salts, potassiumsalts, and ammonium ions (⁺N(R′)₄), where the R′s independentlydesignate optionally substituted C₁₋₆-alkyl, optionally substitutedC₂₋₆-alkenyl, optionally substituted aryl, or optionally substitutedheteroaryl). Pharmaceutically acceptable salts are, e.g., thosedescribed in Remington's —The Science and Practice of Pharmacy, 20th Ed.Alfonso R. Gennaro (Ed.), Lippincott, Williams & Wilkins; ISBN:0683306472, 2000, and in Encyclopedia of Pharmaceutical Technology.However, generally preferred salt forming agents for application in thepresent invention are organic dicarboxylic acids such as oxalic,fumaric, and maleic acid, and the like.

Thus, chalcones with amino groups can be prepared in their salt-formsthereby making the compounds particularly useful for pharmaceuticalformulations. The use of appropriate selected salt form can be used tocontrol the dissolution rate in vivo. Furthermore, the different saltforms have different bulk-properties which is of importance for themanufacturing process.

Preparation of Compounds

The amino-functional chalcones defined herein may be produced by methodsknown per se for the preparation of chalcones or methods which areanalogous to such methods. Examples of excellent methods for preparingcompounds of the 1,3-bis-aromatic-prop-2-enone or the1,3-bis-aromatic-prop-2-ynone types are given in the following. Furtherexamples of methods for the preparation of the compound used accordingto the present invention are described in WO 95/06628 and WO 93/17671and in the references cited therein.

Compounds of the general formula I in which V is —CH═CH— can be preparedby reacting a ketone (an acetophenone in the case where Ar¹ is phenyl)(Y¹)_(m)—Ar¹(X¹)—C(═O)—CH₃

with an aldehyde (a benzaldehyde in the case where Ar² is phenyl)HCO—Ar²(X²)—(Y²)_(p)

wherein Ar¹, Ar^(2,) X¹, X², Y¹, Y², m, and p refer to the definitionsgiven elsewhere herein.

This reaction, which is a condensation reaction, is suitably carried outunder acid or base catalysed conditions. A review of such processes maybe found in Nielsen, A. T., Houlihahn, W. J., Org. React. 16, 1968, p1-444. in particular the method described by Wattanasin, S. and Murphy,S., Synthesis (1980) 647 has been found quite successful. The reactionmay suitably be carried out in protic organic solvents, such as loweralcohols (e.g. methanol, ethanol, or tert-butanol), or lower carboxylicacids (formic, glacial acetic, or propionic acid), or in aprotic organicsolvents such as ethers (e.g. tetrahydrofuran, dioxane, or diethylether), liquid amides (e.g. dimethylformamide orhexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons (e.g.toluene or benzene), or mixtures of such solvents. When carrying out thereaction under base catalysed conditions, the catalyst may be selectedfrom sodium, lithium, potassium, barium, calcium, magnesium, aluminum,ammonium, or quaternary ammonium hydroxides, lower alkoxides (e.g.methoxides, ethoxides, tert-butoxides), carbonates, borates, oxides,hydrides, or amides of lower secondary amines (e.g. diisopropyl amidesor methylphenyl amides). Primary aromatic amines such as aniline, freesecondary amines such as dimethyl amine, diethyl amine, piperidine, orpyrrolidine as well as basic ion exchange resins may also be used.

Acid catalysts may be selected from hydrogen chloride, hydrogen bromide,hydrogen iodide, sulfuric acid, sulfonic acids (such asparatoluenesulfonic or methanesulfonic acid), lower carboxylic acids(such as formic, acetic or propionic acid), lower halogenated carboxylicacids (such as trifluoroacetic acid), Lewis acids (such as BF₃, POCl₃,PCl₅, or FeCl₃), or acid ion exchange resins.

A drawback of the base catalysed condensation is the poor yield obtainedif the aromatic ring in which the ketone or the aldehyde or both issubstituted with one or more hydroxy groups. This drawback can beovercome by masking the phenolic group as described by T. Hidetsugu etal. in EP 0 370 461. Deprotection is easily performed by mineral acidssuch as hydrochloric acid.

The reaction is typically carried out at temperatures in the range of0-100° C., e.g. at room temperature. Reaction times are typically from30 min to 24 hours.

The alkyl- or dialkyl aminomethyl-acetophenones and -benzaldehydes wereprepared by reductive amination using substituted benzaldehyde, amineand sodium triacetoxyborohydride. The alkyl- or dialkylaminoalkyl-acetophenones and -benzaldehydes were prepared from thecorresponding bromo-compounds using halogen/metal exchange (n-BuLi) andquenching with N,N-dimethylacetamide and dimethylformamide,respectively.

Compounds of the general formula I in which V is —C≡C— may be preparedby reacting an activated derivative of a carboxylic acid of the generalformula(Y¹)_(m)—(X¹)Ar¹—COOH

with an ethyne derivativeH—C≡C—Ar²(X²)—(Y²)_(p)wherein Ar¹, Ar², X¹, X², Y¹, Y², m, and p refer to the definitionsgiven elsewhere herein.

Reactions of this type are described by Tohda, Y., Sonogashihara, K.,Haghara, N., Synthesis 1977, p 777-778. It is contemplated that theactivated derivative of the carboxylic acid may be an activated ester,an anhydride or, preferably, an acid halogenide, in particular the acidchloride. The reaction is normally carried out using the catalystsdescribed by Tohda, Y. et al. cited above, namelycopper(I)iodide/triphenylphosphine-palladium dichloride. The reaction issuitably carried out in triethylamine, a mixture of triethylamine andpyridine or triethylamine and toluene under a dry inert atmosphere suchas nitrogen or argon. The reaction is generally carried out at reducedtemperature such as in the range from −80° C. to room temperature, thereaction time typically being from 30 minutes to 6 hours.

In the above reactions, it may be preferred or necessary to protectvarious sensitive or reactive groups present in the starting materialsto prevent said groups from interfering with the reactions. Suchprotection may be carried out in a well-known manner, e.g. as describedin “Protective Groups in Organic Chemistry” by Wuts and Greene,Wiley-Interscience; ISBN: 0471160199; 3nd edition (May 15, 1999). Forexample, in the reaction between the activated acid derivative and theacetylene derivative, a hydroxy group on Ar¹ and/or Ar² may be protectedin the form of the methoxymethyl ether, N,N-dimethylcarbamoyl ester, orallyl ether. The protecting group may be removed after the reaction in amanner known per se.

The ethyne derivative may be prepared by standard methods, e.g. asdescribed by Nielsen, S. F. Et al., Bioorg. Med. Chem. 6, pp 937-945(1998). The carboxylic acids may likewise be prepared by standardprocedures or by reductive amination as described in the examples.

Compounds of the general formula I in which V is —CH₂—CH₂— can beprepared by ionic hydrogenation of the corresponding α,β-unsaturatedcompound where V is —CH═CH— as it has been described by the inventors inNielsen, S. F. et al. Tetrahedron, 53, pp 5573-5580 (1997) and in theexamples (see FIG. 2).

Further possible synthetic routes for the preparation of the saturatedvariants are described in “Advanced Organic Chemistry” by Jerry March,3^(rd) ed. (especially chapter 15, pages 691-700) and references citedtherein. Thus, it is possible to obtain a large variety of compounds ofthe 1,3-bis-aromatic-propan-1-one type from the correspondingprop-2-en-1-ones.

Therapeutic Uses

The present inventors have found that that the novel compound haveinteresting properties as bacteriostatic, bacteriocidal andantiparasitic agents (see the Examples section). It is of coursepossible that the compounds also have other interesting properties to beutilised in the medical field.

Thus, the present invention provides, in a further aspect, a compound(chalcone derivative) as defined herein for use as a drug substance, i.e. a medicament.

Moreover, in further aspects the invention relates to the use of thecompounds as defined herein for the preparation of a medicament for thetreatment of infections, such as infections associated with bacteria,protozoas or Leishmania spp.

The invention also provides in still further aspects a method for thetreatment of infections such as bacteria, protozoas or Leishmania spp ina mammal comprising the administration of the compounds as definedherein to said mammal.

In one aspect, the chalcone derivatives may be used for the treatment ofbacterial infections in a mammal in need thereof. Such bacterialinfection may be associated with common Gram-positive and/orGram-negative pathogenes or with microaerophilic or anaerobic bacteria.As a particularly relevant example of bacteria against which chalconederivatives demonstrates an effect can be mentioned antibiotic-sensitiveor -resistant strains of S. aureus and/or E. faecium. Other examplesinclude community acquired and nosocomial respiratory infections,including S. pneumoniae, S. pyogenes and members of Enterobacteriaceae(e.g. E. coli), microaerophilic bacteria associated with gastric disease(e.g. Helicobacter pylori) or pathogenic anaerobic bacteria (e.g.Bacteroides fragilis and Clostridium species).

In still another aspect, the chalcone derivatives as provided herein canbe used for the treatment of infections associated with protozoa in amammal. Examples of infections are those caused by a protozoa selectedfrom Plasmodium falciparum, Plasmodlum vivax, Plasmodium ovale andPlasmodium malariae.

In a still further aspect, the chalcone derivatives as defined hereincan be used for the treatment of infections in a mammal associated withLeishmania spp. Such infections may be cutaneous and/or visceral.

Preliminary results have shown that compounds wherein the Y¹ is theamino-substituent, i. e. m is one and p is 0, in particular positionedthe 2-, 3- or 4-position, and preferably positioned in the 2-position,where Ar¹ is phenyl, are particularly promising for the treatment ofinfections associated with Leishmania spp. Those in which X² representsat least one substituent selected from C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylcarbonyl, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylamino, optionally substitutedheteroaryl, optionally substituted heteroarylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen, such as where X² represent the 2,4 or 2,5 substituents of aphenyl group as Ar², appear to be particularly promising. Further,embodiments wherein X² represents one or more halogens located in the2-, 3- and/or 4-position, especially in the 2- and/or 4-position,optionally in conjunction with an optionally substituted aryl oroptionally substituted heteroaryl group in the 3- or 5-position aresuitable in this aspect.

Other preliminary results indicate that compounds wherein the Y¹ is theamino-substituent, in particular positioned in the 2-, 3-, or4-position, preferably in the 2- and/or 4-position, where Ar¹ is phenyl,are particularly promising for the treatment of infections caused bymalaria. Those in which X² represents at least one substituent selectedfrom C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylcarbonyl, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylamino,optionally substituted heteroaryl, optionally substitutedheteroarylamino, optionally substituted (heteroarylalkyl)amino,optionally substituted (heteroarylalkyl)alkylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen, such as where X² represent the 2,5 substituents of a phenylgroup as Ar², appear to be particularly promising. Further, suitableembodiments are those in which X¹ is hydrogen, methoxy or hydroxy. Yetfurther particularly useful embodiments are those wherein X² representsone or two halogen atoms, such as chloro, located in the 2- and/or4-positions. Another interesting embodiment is the one wherein X²represents two substituents, located in the 2- and 5-positions,independently selected from alkoxy, alkyl, aryl, dialkylamino andpyridinylamino, with methoxy being a preferred alkoxy group. When X²represents one substituent, especially interesting compounds have X²located in the 3- or 4-position, and selected from mono- ordi-alkylamino, pyridinylamino, imidazolyl and halogen, the latter beingparticularly suitable in the 4-position. Typical embodiments wherein X²represents three substituents are those wherein these substituents arelocated in the 2-, 4-, and 5-positions, such as 2-alkoxy, 4-alkoxy,hydroxy or halo, and 5-alkyl or aryl, as well as those wherein the threesubstituents are located in the 2-, 3-, and 5-positions, such as2-alkoxy or alkyl, 3-alkoxy or alkyl, and 5-alkoxy or alkyl. In thecontext of treating infections associated with malaria, further,preferred meanings of R are alkyl, especially methyl.

Additionally, embodiments wherein both m and p are 1 are suitable fortreatment of infections associated with malaria. Such embodimentstypically have Y² in the 2-, 3-, or 5-position.

Embodiments in which m is 0 and p is 1 are currently interesting for thetreatment of infections associated with malaria. Those typically have Y²in the 2-, 3-, or 4-position when Ar² is phenyl. Preferred suchcompounds are those where Y² is located at the 2-position, with furtheroptional presence (X²) of a 5-aryl substituent. Additionally, typicalmeanings of X¹ in this context are 2- and/or 4-halo and 2- and/or4-alkoxy, with 4-methoxy and 2-fluoro being preferred.

Still other preliminary results indicate that compounds wherein the Y¹is the amino-substituent, in particular positioned in the 2, 3 or 4position where Ar¹ is phenyl, are particularly promising for thetreatment of infections caused by S. aureus. Those in which X²represents at least one substituent selected from C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-alkylcarbonyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted arylamino, optionallysubstituted heteroaryl, optionally substituted heteroarylamino, mono-and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen appear to be particularly promising.

Formulation of Pharmaceutical Compositions

The chalcone derivatives are typically formulated in a pharmaceuticalcomposition prior to use as a drug substance.

The administration route of the compounds as defined herein may be anysuitable route which leads to a concentration in the blood or tissuecorresponding to a therapeutic effective concentration. Thus, e.g., thefollowing administration routes may be applicable although the inventionis not limited thereto: the oral route, the parenteral route, thecutaneous route, the nasal route, the rectal route, the vaginal routeand the ocular route. It should be clear to a person skilled in the artthat the administration route is dependent on the particular compound inquestion, particularly, the choice of administration route depends onthe physico-chemical properties of the compound together with the ageand weight of the patient and on the particular disease or condition andthe severity of the same.

The compounds as defined herein may be contained in any appropriateamount in a pharmaceutical composition, and are generally contained inan amount of about 1-95% by weight of the total weight of thecomposition. The composition may be presented in a dosage form which issuitable for the oral, parenteral, rectal, cutaneous, nasal, vaginaland/or ocular administration route. Thus, the composition may be in formof, e.g., tablets, capsules, pills, powders, granulates, suspensions,emulsions, solutions, gels including hydrogels, pastes, ointments,creams, plasters, drenches, delivery devices, suppositories, enemas,injectables, implants, sprays, aerosols and in other suitable form.

The pharmaceutical compositions may be formulated according toconventional pharmaceutical practice, see, e.g., “Remington'sPharmaceutical Sciences” and “Encyclopedia of PharmaceuticalTechnology”, edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker,inc., New York, 1988. Typically, the compounds defined herein areformulated with (at least) a pharmaceutically acceptable carrier orexipient. Pharmaceutically acceptable carriers or exipients are thoseknown by the person skilled in the art.

Thus, the present invention provides in a further aspect apharmaceutical composition comprising a compound as defined herein incombination with a pharmaceutically acceptable carrier.

Pharmaceutical compositions according to the present invention may beformulated to release the active compound substantially immediately uponadministration or at any substantially predetermined time or time periodafter administration. The latter type of compositions are generallyknown as controlled release formulations.

In the present context, the term “controlled release formulation”embraces i) formulations which create a substantially constantconcentration of the drug within the body over an extended period oftime, ii) formulations which after a predetermined lag time create asubstantially constant concentration of the drug within the body over anextended period of time, iii) formulations which sustain drug actionduring a predetermined time period by maintaining a relatively,constant, effective drug level in the body with concomitant minimizationof undesirable side effects associated with fluctuations in the plasmalevel of the active drug substance (sawtooth kinetic pattern), iv)formulations which attempt to localize drug action by, e.g., spatialplacement of a controlled release composition adjacent to or in thediseased tissue or organ, v) formulations which attempt to target drugaction by using carriers or chemical derivatives to deliver the drug toa particular target cell type.

Controlled release formulations may also be denoted “sustained release”,“prolonged release”, “programmed release”, “time release”,“rate-controlled” and/or “targeted release” formulations.

Controlled release pharmaceutical compositions may be presented in anysuitable dosage forms, especially in dosage forms intended for oral,parenteral, cutaneous nasal, rectal, vaginal and/or ocularadministration. Examples include single or multiple unit tablet orcapsule compositions, oil solutions, suspensions, emulsions,microcapsules, microspheres, nanoparticles, liposomes, delivery devicessuch as those intended for oral, parenteral, cutaneous, nasal, vaginalor ocular use.

Preparation of solid dosage forms for oral use, controlled release oraldosage forms, fluid liquid compositions, parenteral compositions,controlled release parenteral compositions, rectal compositions, nasalcompositions, percutaneous and topical compositions, controlled releasepercutaneous and topical compositions, and compositions foradministration to the eye can be performed essentially as described inthe applicant's earlier International application No. WO 99/00114, page29, line 9, to page 40, line 3. Also, and more generally, theformulation and preparation of the above-mentioned compositions arewell-known to those skilled in the art of pharmaceutical formulation.Specific formulations can be found in “Remington's PharmaceuticalSciences”.

Dosages

The compound are preferably administered in an amount of about 0.1-50 mgper kg body weight per day, such as about 0.5-25 mg per kg body weightper day.

For compositions adapted for oral administration for systemic use, thedosage is normally 2 mg to 1 g per dose administered 1-4 times daily for1 week to 12 months depending on the disease to be treated.

The dosage for oral administration for the treatment of parasiticdiseases is normally 1 mg to 1 g per dose administered 1-2 times dailyfor 1-4 weeks, in particular the treatment of malaria is to be continuedfor 1-2 weeks whereas the treatment of leishmaniasis will normally becarried out for 3-4 weeks.

The dosage for oral administration for the treatment of bacterialdiseases is normally 1 mg to 1 g per dose administered 1-4 times dailyfor 1 week to 12 months; in particular, the treatment of tuberculosiswill normally be carried out for 6-12 months.

The dosage for oral administration of the composition in order toprevent diseases is normally 1 mg to 75 mg per kg body weight per day.The dosage may be administered once or twice daily for a period starting1 week before the exposure to the disease until 4 weeks after theexposure.

For compositions adapted for rectal use for preventing diseases, asomewhat higher amount of the compound is usually preferred, i.e. fromapproximately 1 mg to 100 mg per kg body weight per day.

For parenteral administration, a dose of about 0.1 mg to about 50 mg perkg body weight per day is convenient. For intravenous administration adose of about 0.1 mg to about 20 mg per kg body weight per dayadministered for 1 day to 3 months is convenient. For intraarticularadministration a dose of about 0.1 mg to about 20 mg per kg body weightper day is usually preferable. For parenteral administration in general,a solution in an aqueous medium of 0.5-2% or more of the activeingredients may be employed.

For topical administration on the skin, a dose of about 1 mg to about 5g administered 1-times daily for 1 week to 12 months is usuallypreferable.

In many cases, it will be preferred to administer the compound definedherein together with another antiparasitic, antimycotic or antibioticdrug, thereby reducing the risk of development of resistance against theconventional drugs, and reducing the amount of each of the drugs to beadministered, thus reducing the risk of side effects caused by theconventional drugs. Important aspects of this is the use of the compoundagainst Leishmania, where the compound I is combined with anotherantileishmanial drug, or the antimalarial use of the compound I wherethe compound I is used together with another antimalarial drug.

Method of Prediction

In a separate aspect, the present invention also provides a method ofpredicting whether a chemical compound has a potential inhibitory effectagainst a microorganism selected from Helicobacter pylori and Plasmodiumfalciparum, said method comprising preparing a mixture of adihydroorotate dehydrogenase, a substrate for dihydroorotatedehydrogenase and the chemical compound, measuring the enzymaticactivity of dihydroorotate dehydrogenase (A), comparing the enzymaticactivity of dihydroorotate dehydrogenase (A) with the standard activityof dihydroorotate dehydrogenase (B) corresponding to the activity of adihydroorotate dehydrogenase in a similar sample, but without thechemical compound, predicting that the chemical compound has a potentialinhibitory effect against Helicobacter pylon and Plasmodium falciparumif A is significantly lower than B.

The method can be performed as described under DHODH Assay in theExamples section. It should be noted that the method is not onlyapplicable for the chalcone derivatives defined herein, but can begenerally applied to predict the potential inhibitory effect of anycompound. Preferably, however, the chemical compound is a chalconederivative, e.g. a chalcone derivative as defined herein.

EXAMPLES

Preparation of Compounds

Chemical names presented below were generated using the softwareChemDraw Ultra, version 6.0.1, from CambridgeSoft.com.

The general method for the preparation of the A ring or B ring havingthe amino-functional group is illustrated in FIG. 1.

General Procedure A

Preparation of alkyl- or dialkyl aminomethyl acetophenones

To a solution of 2-methyl-[1,3]dioxan-2-yl benzaldehyde (165 mmol) andamine (247 mmol) in dry THF (1.5 L) was added sodiumtriacetoxyborohydride (257 mmol) under argon. The resulting suspensionwas stirred at room temperature for 18 hr. A solution of sodiumhydroxide (2M) was added and stirring was continued for approximately 30min, before the mixture was acidified using HCl (6M). The mixture wasstirred for 1 hr. and extracted with diethyl ether, which was discarded.The pH of the aqueous phase was adjusted to 11-14 using sodium hydroxideand extracted again with diethyl ether. The latter organic phase, wasdried over sodium sulphate, filtered and evaporated to give the titleproducts, which were used without further purification. GeneralProcedure B

Preparation of alkyl- or dialkyl aminomethyl benzaldehydes

To a solution of diethoxymethyl benzaldehyde (16.5 mmol) and amine (24.7mmol) in dry THF (150 mL) was added sodium triacetoxyborohydride (25.7mmol) under argon. The resulting suspension was stirred at roomtemperature for 6-18 hr. A solution of sodium hydroxide (2M) was addedand stirring was continued for approximately 30 min, before the mixturewas acidified using HCl (6M). The mixture was stirred for 1 hr. andextracted with diethyl ether, which was discarded. The pH of the aqueousphase was adjusted to 11-14 using sodium hydroxide and extracted againwith diethyl ether. The latter organic phase, was dried over sodiumsulphate, filtered and evaporated to give the title products, which wereused without further purification.

General Procedure C

Preparation of biaryl carbaldehydes

A solution of Na₂CO₃ (44 mmol) in water (20 mL) was added to a solutionof bromobenzaldehyde (14.7 mmol) and arylboronic acid (17.6 mmol) in DME(40 mL). The mixture was flushed with argon for 2 minutes followed byaddition of Pd(PPh₃)₂Cl₂ (310 mg, 3 mol %). The reaction was heated atreflux and left overnight under an atmosphere of argon. The reaction wascooled, 2M Na₂CO₃ was added, and the mixture was extracted with EtOAc(3×20 mL). The title products were purified by flash chromatography.

General Procedure D

Preparation of amino benzaldehydes

Bromobenzaldehyde diethyl acetal (40 mmol), amine (48 mmol), Pd₂(dba)₃(0.2 mmol, 1 mol % Pd), rac-BINAP (0.6 mmol) and t-BuONa (68 mmol) wasstirred in degassed toluene (60 mL) at 80° C. for 18 h. The darkbrownmixture was poured into icecold hydrochloric acid (1 M, 200 mL) andstirred vigorously for 2 hours at 25° C. The solution was cooled to 0°C. and pH was adjusted to 10 using 6M NaOH(aq) and extracted with Et₂O(4×100 mL). The organic phase was dried (K₂CO₃) and the solvent wasremoved under reduced pressure. The resulting crude oil purified byflash chromatography using 5% Et₃N in EtOAc

General Procedure E

Preparation of aminochalcones with phenolic substituents

To a solution of an acetophenone (2 mmol) and a tetrahydro-pyran-2-yloxybenzaldehyde (2 mmol) in 96% EtOH (10 mL) was added 8M NaOH (0.3 mL),and the mixture was stirred for 3-18 hours at 25° C. The mixture wasevaporated on Celite® and the product was isolated by flashchromatography. The aminochalcone was dissolved in MeOH:Et₂O (1:9 v/v,10 mL) and a solution of fumaric acid or oxalic acid in MeOH:Et₂O (1:9v/v) was added. The salt was filtered off. Hydrolysis of thetetrahydropyran ether was carried out by adding H₂O and MeOH andstirring at reflux for 72 hr. The salts of the phenolic aminochalconeswere isolated by evaporation. Some aminochalcones did not undergo saltformation, and was isolated as the free base, by extraction from aqueousNaHCO₃. The purity was >95% determined by HPLC and the molecular weightwas determined by LC-MS.

General Procedure F

Preparation of aminochalcones from acetophenones and aldehydes

To a solution of an acetophenone (2 mmol) and a benzaldehyde (2 mmol) in96% EtOH (10 mL) was added NaOH (0.2 mmol), and the mixture was stirredfor 3-18 hours at 25° C. The mixture was evaporated on Celite® and theproduct was isolated by flash chromatography. The aminochalcone wasdissolved in MeOH:Et₂O (1:9 v/v, 10 mL) and a solution of fumaric acidor oxalic acid in MeOH:Et₂O (1:9 v/v) was added. The salt was filteredoff and recrystallised from MeOH or MeCN. Some aminocalcones did notundergo salt formation, and was isolated as the free base. The puritywas >95% determined by HPLC.

General Procedure G

Preparation of formylchalcones, substituted in the A-ring

A solution of 1-(diethoxymethyl-phenyl)-ethanone (29 mmol), anbenzaldehyde (29 mmol), and NaOH (2.9 mmol) in 96% EtOH (100 mL) wasstirred for 18 hours at 25° C. 6M HCl (10 mL) and Et₂O (50 mL) was addedand the solution was stirred for 5 hours at 25° C. H₂O (50 mL) and themixture was extracted with Et₂O. The organic phases were pooled, driedover Na₂SO₄, and filtered. Evaporation gave the crude title product,which was purified by flash chromatography or crystallization.

General Procedure H

Preparation of formylchalcones, substituted in the B-ring

A solution of diethoxymethyl-benzaldehyde (42 mmol), an acetophenone (42mmol), and sodium hydroxide (8 mmol) in 96% EtOH (100 mL) was stirredfor 18 hours at 25° C. 6M HCl (10 mL) and Et₂O (50 mL) was added and thesolution was stirred for 5 hours at 25° C. H₂O (50 mL) and the mixturewas extracted with Et₂O. The organic phases were pooled, dried overNa₂SO₄, and filtered. Evaporation gave the crude title product, whichwas purified by flash chromatography or crystallization.

General Procedure I

Preparation of aminochalcones from formylchalcones

To a solution of an formylchalcone (3.8 mmol) and amine (5.6 mmol) indry THF (40 mL) was added sodium triacetoxyborohydride (5.6 mmol) underargon. The resulting suspension was stirred at room temperature for 6-18hr. A solution of sodium hydroxide (2M) was added and stirring wascontinued for approximately 30 min, before the mixture extracted withethyl acetate. The organic phase, was dried over sodium sulphate,filtered, and evaporated on Celite®. The product was isolated by flashchromatography. The purity was >95% determined by HPLC.

Characterisation of the Compounds

The compounds were characterised by NMR (300 MHz) and GC-MS/LC-MS.

Acetophenones

1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-ethanone

General procedure A gave the title product as brown oil in 78% yield.¹H-NMR (CDCl₃,): δ 7.42-7.29 (m, 4H), 3.65 (s, 2H), 2.54 (s, 3H), 2.43(b, 8H), 2.27 (s, 3H).

1-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-ethanone

General procedure A gave the title product as yellow oil in 18% yield.¹H-NMR (CDCl₃): δ 7.91 (d, 2H), 7.42 (d, 2H), 3.85 (s, 2H), 2.68 (t,2H), 2.60 (s, 3H), 2.36 (t, 2H), 2.22 (s, 6H), 1.73-1.62 (m, 2H).

1-(3-Diethylaminomethyl-phenyl)-ethanone

General procedure A gave the title product as yellow oil in 80% yield.¹H-NMR (CDCl₃): δ 7.91 (s, 1H), 7.82 (d, 1H), 7.57 (d, 1H), 7.40 (t,1H), 3.61 (s, 2H), 2.61 (s, 3H), 2.52 (t, 4H), 1.04 (t, 6H).

1-(3-Dimethylaminomethyl-phenyl)-ethanone

General procedure A gave the title product as yellow oil in 89% yield.¹H-NMR (CDCl₃): δ 7.89 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.42 (t,1H), 3.47 (s, 2H), 2.61 (s, 3H), 2.25 (s, 6H).

1-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-ethanone

General procedure A gave the title product as brown oil in 88% yield.¹H-NMR (DMSO) δ 7.51 (d, 1H), 7.40-7.30 (m, 3H), 3.57 (s, 2H), 2.56 (s,3H), 2.39-2.32 (m, 2H), 2.99-2.23 (m, 2H), 2.07 (s, 6H), 2.03 (s, 3H).

1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-ethanone

General procedure A gave the title product as brown oil in 44% yield.¹H-NMR (DMSO) δ 7.52 (dd, 1H), 7.51 (dd, 1H), 7.40 (td, 1H), 7.30 (td,1H), 3.63 (s, 2H), 2.48 (s, 3H), 1.91 (s, 3H), 1.03 (s, 9H).

1-[2-(4-Hydroxy-piperidin-1-ylmethyl)-phenyl]-ethanone

General procedure A gave the title product as brown oil in 82% yield.¹H-NMR (CDCl₃) δ 7.32 (dt, 1H), 7.28-7.19 (m, 3H), 3.65-3.56 (m, 1H),3.54 (s, 2H), 2.63-2.55 (m, 2H), 2.45 (s, 3H), 2.10-2.01 (m, 2H),1.79-1.70 (m, 2H), 1.49-1.36 (m, 2H).

1-(2-Morpholin-4-ylmethyl-phenyl)-ethanone

General procedure A gave the title product as yellow oil in 89% yield.Pure according to GCMS m/z: 219.

1-[4-Hydroxy-3-(4-methyl-piperazin-1-yl methyl)-phenyl]-ethanone

A solution of formaldehyde (37% w/w, 8.2 mL) was added to a solution of4′-Hydroxy acetophenone (100 mmol), and N-methylpiperazine (110 mmol) inEtOH. Heated at reflux overnight. The solvent was evaporated on celiteand the residue was purified by flash chromatography and crystallizedfrom heptane to give the title product as white needles in 55% yield.¹H-NMR (DMSO) δ 7.76 (dd, 1H), 7.74 (s, 1H), 6.81 (d, 1H), 3.69 (s, 2H),2.47 (br, 4H), 2.46 ((s, 3H), 2.35 (br, 4H), 2.17 (s, 3H).

1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-ethanone

(5-Bromo-2-methoxy-benzyl)-dimethyl-amine (29 mmol), Butoxy-ethene (100mmol), Palladium acetate (0.9 mmol), 1,3-Bis(diphenylphosphino) propane(1.8 mmol), and potassium carbonate were suspended in DMF (50 ml) andH₂O under argon. Heated at 80° C. overnight. Poured into hydrochloricacid (2 M) and stirred for 1 hour. The mixture was adjusted to basic pHand extracted with CH₂Cl₂. The organic phase was evaporated on celiteand the residue was purified by flash chromatography to give the titleproduct as orange oil in 42% yield. ¹H-NMR (CDCl₃) δ 7.90 (s, 1H), 7.88(dd, 1H), 6.89 (d, 1H), 3.88 (s, 3H), 3.44 (s, 2H), 2.55 (s, 3H), 2.25(s, 6H).

Benzaldehydes

2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-benzaldehyde

General procedure B gave the title product as brown oil in 82% yield.¹H-NMR (CDCl₃): δ 10.48 (s, 1H), 7,89 (dd, 1H), 7.53-7.24 (m, 3H), 3.87(s, 2H), 2.55 (t, 2H), 2.44 (t, 2H), 2.23-2.18 (m, 9H).

2-(4-Methyl-piperazin-1-ylmethyl)-benzaldehyde

General procedure B gave the title product as brown oil in 80% yield.¹H-NMR (CDCl₃): δ 10.41 (s, 1H), 7.87 (d, 1H), 7.51 (dt, 1H)7.41 (t,1H), 7.38 (d, 1H), 3.81 (s, 2H), 2.6-2.3 (m, 8H), 2.27 (s, 3H).

3-Dimethylaminomethyl-4-methoxy-benzaldehyde

To a solution of 4-bromo-2-(dimethylaminomethyl)anisole (12.2 g, 50mmol) in dry THF (150 mL) at −78° C. was added n-BuLi (2.5 M, 20 mL, 50mmol) keeping the temperature below −70° C. The orange mixture wasstirred for 15 min and dry DMF (4.7 mL, 60 mmol) was added in oneportion. The cooling bath was removed and the light yellow mixture wasallowed to warm to 20° C. After 30 min the mixture was hydrolysed with5% Na₂CO₃ (100 mL), and extracted with Et₂O (3×100 mL). The organicphase was dried (K₂CO₃) and the solvent was removed under reducedpressure leaving yellow oil (79%) that was pure enough for furtherreaction. ¹H-NMR(DMSO-d₆): δ 9.87 (s, 1H), 7.88-7.40 (m, 1H), 7.81 (d,1H), 7.19 (d, 1H), 3.88 (s, 3H), 3.42 (s, 2H), 2.17 (s, 6H).

3-(Pyridin-3-ylamino)-benzaldehyde

General procedure D gave the title compound as white crystals in 69%yield.¹H-NMR(DMSO-d₆): δ 9.94 (s, 1H), 8.67 (s, 1H), 8.40 (d, 1H), 8.11(dd, 1H), 7.58-7.50 (m, 2H), 7.47 (d, 1H), 7.43-7.35 (m, 2H), 7.29 (dd,1H).

3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-benzaldehyde

General procedure B gave the title product as yellow oil in 84% yield.¹H-NMR (CDCl₃): δ 10.04 (s, 1H), 7.82 (m, 2H), 7.62 (dt, 1H), 7.52 (t,1H), 3.67 (m, 4H), 2.64 (t, 2H), 2.26 (s, 2H).

3-[(2-Methoxy-ethylamino)-methyl]-benzaldehyde

General procedure B gave the title product as yellow oil in 24% yield.¹H-NMR (CDCl₃): δ 10.04, (s, 1H), 7.89 (t, 1H), 7.79 (dt, 1H), 7.65 (dt,1H), 7.51 (t, 1H), 3.92 (s, 2H), 3.55 (t, 2H), 3.39 (s, 3H), 2.84 (t,2H), 1.79 (s, 1H).

4-Diethylaminomethyl-benzaldehyde

General procedure B gave the title product as brown oil in 74% yield.¹H-NMR (CDCl₃): δ 10.02 (s, 1H), 7.85 (d, 2H), 7.55 (d, 2H), 3.66 (s,2H), 2.56 (k, 4H), 1.07 (t, 6H).

3-Butylamino-benzaldehyde

General procedure D gave the title compound as yellow oil in 78 % yield.¹H-NMR(DMSO-d₆): δ 9.90 (s, 1H), 7.34 (t, 1H), 7.21 (s, 1H), 7.15-7.05(m, 2H), 6.96 (dd, 1H), 3.30 (t, 2H), 1.57-1.42 (m, 2H), 1.40-1.25 (m,2H), 0.92 (t, 3H).

4-Dibutylamino-2-fluoro-benzaldehyde

General procedure B gave the title product as yellow oil in 56% yield.¹H-NMR (CDCl₃): δ 10.02 (s, 1H), 7.68 (t, 1H), 6.23 (d, 1H), 6.18 (d,1H), 3.29 (t, 4H), 1.71-1.57 (m, 4H), 0.96 (t, 6H).

4-Methoxy-3′,5′-dimethyl-biphenyl-3-carbaldehyde

General procedure C gave the title compound as white crystals in 81%yield. ¹H-NMR(CDCl₃): δ 10.41 (s, 1H), 8.00 (d, 1H), 7.68 (dd, 1H), 7.31(s, 2H), 7.19 (d, 1H), 6.93 (s, 1H), ), 4.25 (t, 2H), 2.81 (t, 2H), 2.38(s, 6H), 2.26 (s, 6H).

3-(Butyl-ethyl-amino)-benzaldehyde

General procedure D gave the title compound as yellow oil in 40% yield.¹H-NMR(DMSO-D₆): δ 9.90 (s, 1H), 7.35 (t, 1H), 7.12-7.05 (m, 2H), 6.96(dd, 1H), 3.39 (q, 2H), 3.30 (t, 2H), 1.57-1.42 (m, 2H), 1.40-1.25 (m,2H), 1.08 (t, 3H), 0.92 (t, 3H).

4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzaldehyde2-(2-Chloro-4-methoxy-phenyl)propionitrile

A solution of 2′-chloro-4′-methoxyacetophenone (18.5 g, 0.10 mol) andtosylmethylisocyanide (TOSMIC, 21.5 g, 0.11 mol) in dry1,2-dimethoxyethane (100 mL) was cooled to −10° C. A solution of t-BuOK(22.4 g, 0.20 mol) in dry t-BuOH (250 mL) was added slowly keeping thetemperature below 5° C. The homogeneous orange solution was stirred for2 h/0° C. and 1 h/25° C. The resulting suspension was evaporated to aslurry. Water (200 mL) was added and extracted with Et₂O (3×150 mL). Theorganic phase was dried (Na₂SO₄) and the solvent was removed underreduced pressure leaving an orange oil. Yield: 19 g (97%). GCMS: >98%;¹H-NMR(DMSO-d₆): δ 7.49 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 4.42 (q,1H), 3.80 (s, 3H), 1.55 (d, 3H).

2-(2-Chloro-4-methoxy-phenyl)-2-methyl-propionitrile

A solution of 2-(2-chloro-4-methoxy-phenyl)propionitrile (19 g, 0.097mol) and methyliodide (7 mL, 0.11 mol) in dry DMF (100 mL) was flushedwith argon for 2 min and cooled to 0° C. Sodium hydride (60% oil susp.,4.4 g, 0.11 mol) was added in small portions. The thick suspension wasstirred for another 18 h at 25° C. and then poured into water (300 mL)and extracted with Et₂O (3×100 mL). The organic phase was dried (Na₂SO₄)and the solvent was removed under reduced pressure leaving a yellow oilwhich was distilled. Bp: 103-106° C./0.06 mbar, clear oil thatsolidifies on standing. Yield: 17.5 g (83%). GCMS: >99%;¹H-NMR(DMSO-d₆): δ 7.43 (d, 1H), 7.13 (d, 1H), 6.98 (dd, 1H), 3.80 (s,3H), 1.77 (s, 6H).

2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile

A solution of 2-(2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (17.5g, 0.0835 mol) in TFA (100 mL) was cooled to 0° C. N-bromosuccinimide(14.9 g, 0.0835 mol) was added in small portions keeping the temperaturebelow 5° C. The orange solution was stirred for 2 h/25° C. andevaporated to dryness. Water (200 mL) was added and the mixture wasstirred vigorously for 1 h. The crude product was filtered off andrecrystallized from boiling MeOH. The pure product was isolated as whiteneedles. Yield: 13 g (54%). GCMS: >99% ¹H-NMR(DMSO-d₆): δ 7.56 (s, 1H),7.23 (s, 1H), 3.84 (s, 3H), 1.70 (s, 6H).

2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionaldehyde

A solution of2-(5-bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (13 g,0.045 mol) in dry THF (80 mL) was cooled to −10° C. under argon. DIBALH(1M in THF, 100 mL, 0.10 mol) was added keeping the temperature below 0°C. The mixture was stirred for 30 min/0° C. and then 2 h/25° C. Theclear solution was carefully poured into icecold hydrochloric acid (2M,100 mL). The THF was removed under reduced pressure. The aqueous phasewas cooled and the crude product was filtered off and recrystallizedfrom boiling MeOH. Yield: 7.8 g (59%). GCMS: >99%; ¹H-NMR(DMSO-d₆): δ9.61 (s, 1H), 7.68 (s, 1H), 7.27 (s, 1H), 3.89 (s, 3H), 1.40 (s, 6H).

1-Bromo-4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzene

A suspension of methyltriphenylphosphonium bromide (11.4 g, 0.032 mol)in dry THF (100 mL) was cooled to 0° C. under argon. n-BuLi (2.5M, 12mL, 0.030 mol) was added slowly. The suspension became more homogenous.The resulting clear orange solution of the ylide was stirred for another15 min at 0° C.2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionaldehyde (7.8 g,0.027 mol) was dissolved in dry THF (50 mL) and added to ylide-solution.The mixture was stirred for 3 h/25° C. and the resulting suspension wasquenched with MeOH (10 mL). The solvent was removed under reducedpressure and the crude product was purified by flash chromatographyusing n-heptane as eluent. Yield: 3.92 g (50%). GCMS: >99%;¹H-NMR(DMSO-d₆): δ 7.55 (s, 1H), 7.14 (s, 1H), 6.05 (dd, 1H), 5.04 (dd,1H), 4.92 (dd, 1H), 3.87 (s, 3H), 1.45 (s, 6H).

4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzaldehyde

To a solution of1-bromo-4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzene (3.92 g,0.0135 mol) in dry THF (30 mL) was cooled to −78° C. under argon. n-BuLi(2.5M, 6 mL, 0.0145 mol) was added keeping the temperature below −70° C.The yellow mixture was stirred for another 15 min and quenched with dryDMF (1.2 mL, 0.015 mol). The cooling bath was removed and the mixturewas allowed to warm to 25° C. A saturated solution of NaHCO₃ (30 mL) wasadded and then extracted with EtOAc (3×50 mL). The organic phase wasdried (Na₂SO₄) and evaporated to dryness. The crude product wasrecrystallized from MeOH. Yield: 3.00 g (93%). GCMS: >99%;¹H-NMR(DMSO-d₆): δ 10.30 (s, 1H), 7.80 (s, 1H), 7.30 (s, 1H), 6.08 (dd,1H), 5.06 (dd, 1H), 4.91 (dd, 1H), 3.93 (s, 3H), 1.49 (s, 6H).

5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionitrile

A solution of 2-(4-methoxy-phenyl)-2-methyl-propionitrile (17.5 g, 0.10mol) in TFA (80 mL) was cooled to 0° C. N-bromosuccinimide (17.8 g, 0.10mol) was added in small portions keeping the temperature below 5° C. Theorange solution was stirred for 2 h/25° C. and evaporated to dryness.Water (200 mL) was added and the mixture was stirred vigorously for 1 h.The crude product was filtered off and recrystallized from boiling MeOH.The pure product was isolated as white needles. Yield: 19.3 g (76%).GCMS: >99%; ¹H-NMR(DMSO-d₆): δ 7.68 (d, 1H), 7.50 (dd, 1H), 7.16 (d,1H), 3.86 (s, 3H), 1.70 (s, 6H).

2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionaldehyde

A solution of 2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (12.71g, 0.050 mol) in dry THF (100 mL) was cooled to −10° C. under argon.DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the temperaturebelow 0° C. The mixture was stirred for 30 min/0° C. and then 2 h/25° C.The clear solution was carefully poured into icecold hydrochloric acid(2M, 100 mL). The THF was removed under reduced pressure to give clearoil. The oil was destilled (b.p. 114-130° C./4.3×10⁻³ mbar) Yield: 7.40g (58%). GCMS: >99%; ¹H-NMR(CDCl₃): δ 9.44 (s, 1H), 7.45 (d, 1H), 7.15(dd, 1H), 6.90 (d, 1H), 3.89 (s, 3H), 1.43 (s, 6H).

2-Bromo-4-(1,1-dimethyl-allyl)-1-methoxy-benzene

A suspension of methyltriphenylphosphonium bromide (7.71 g, 0.0215 mol)in dry THF (100 mL) was cooled to 0° C. under argon. n-BuLi (2.5M, 8 mL,0.020 mol) was added slowly. The resulting clear orange solution of theylide was stirred for another 15 min at 0° C.2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionaidehyde (3.7 g, 0.014 mol)was dissolved in dry THF (50 mL) and added to ylide-solution. Themixture was stirred for 3 h/25° C. and the resulting suspension wasquenched with MeOH (10 mL). The solvent was removed under reducedpressure and the crude product was purified by flash chromatographyusing n-heptane as eluent. Yield: 3.1 g (84%). GCMS: >99%;¹H-NMR(CDCl₃): δ 7.50 (d, 1H), 7.23 (dd, 1H), 6.83 (d, 1H), 5.97 (dd,1H), 5.06 (dd, 1H), 5.02 (dd, 1H), 3.87 (s, 3H), 1.44 (s, 6H).

5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde

To a solution of 2-Bromo-4-(1,1-dimethyl-allyl)-1-methoxy-benzene (3.1g, 0.012 mol) in dry THF (50 mL) was cooled to −78° C. under argon.n-BuLi (2.5M, 5.1 mL, 0.0128 mol) was added keeping the temperaturebelow −70° C. The yellow mixture was stirred for another min andquenched with dry DMF (1.4 mL, 0.018 mol). The cooling bath was removedand the mixture was allowed to warm to 25° C. A saturated solution ofNaHCO₃ (30 mL) was added and then extracted with EtOAc (3×50 mL). Theorganic phase was dried (Na₂SO₄) and evaporated to yellow oil. Yield:2.31 g (94%). ¹H-NMR(CDCl₃): δ 10.48 (s, 1H), 7.84 (d, 1H), 7.55 (dd,1H), 6.94 (d, 1H), 6.00 (dd, 1H), 5.05 (dd, 1H), 5.01 (dd, 1H), 3.93 (s,3H), 1.41 (s, 6H).

3-Morpholin-4-ylmethyl-benzaldehyde

General procedure B gave the title product as yellow oil in 71% yield.¹H-NMR (CDCl₃): δ 10.05 (s, 1H), 7.88 (s, 1H), 7.81 (d, 1H), 7.64 (d,1H), 7.51 (t, 1H), 3.74 (t, 4H), 3.58 (s, 2H), 2.48 (t, 4H).

2-Methoxy-5-(pyridin-3-ylamino)-benzaldehyde

General procedure D gave the title product as yellow oil thatprecipitated on standing in 39% yield. ¹H-NMR (CDCl₃): δ 10.42 (s, 1H),8.27 (d, 1H), 8.08 (dd, 1H), 7.55 (d, 1H), 7.33 (dd, 1H), 7.26 (ddd,1H), 7.11 (dd, 1H), 6.95 (d, 1H), 6.34 (bs, 1H), 3.90 (s, 3H).

4-Dimethylaminomethyl-biphenyl-3-carbaldehyde

Biphenyl-4-ylmethyl-dimethyl-amine (55 mmol) was dissolved in diethylether and a solution of n-BuLi (65 mmol) was added. Heated at reflux for6 hours under argon. The solution was cooled on ice-bath, before DMF (60mmol) was added. Stirred overnight. Aqueous work-up and vacuumdestillation (b.p. 130-145° C./0.015 mbar) gave the title product asyellow oil in 40% yield. ¹H-NMR (DMSO) δ 10.38 (s, 1H), 8.03 (d, 1H),7.89 (dd, 1H), 7.73-7.69 (m, 2H), 7.53-7.39 (m, 4H), 3.76 (s, 2H), 2.17(s, 6H).

3′,5′-Dichloro-4,6-dimethoxy-biphenyl-3-carbaldehyde

General procedure C gave the title product as beige powder in 54% yield.¹H-NMR (DMSO) δ 10.22 (s, 1H), 7.62 (s, 1H), 7.55 (t, 1H), 7.48 (d, 2H),6.87 (s, 1H), 4.02 (s, 3H), 3.96 (s, 3H).

3-(Pyridin-4-ylamino)-benzaldehyde

General procedure D gave the title product as brown crystals in 11%yield. ¹H-NMR (d₆-DMSO): δ 9.99 (s, 1H), 9.07 (s, 1H), 8.25 (d, 2H),7.78 (s, 1H), 7.57-7.51 (m, 3H), 6.97 (d, 2H).

3-[(Pyridin-3-ylmethyl)-amino]-benzaldehyde

General procedure D gave the title product as brown crystals in 87%yield. ¹H-NMR (d₆-DMSO): 9.85 (s, 1H), 8.61 (d, 1H), 8.45 (dd, 1H), 7.76(dt, 1H), 7.35 (dd, 1H), 7.29 (t, 1H), 7.11-7.08 (m, 2H), 6.95 (dd, 1H),6.71 (t, 1H), 4.37 (d, 2H).

Formylchalcones

(E)-2-[3-(2-Bromo-phenyl)-3-oxo-propenyl]-benzaldehyde

General procedure H gave the title product as yellow crystals in 47%yield. ¹H-NMR (CDCl₃): δ 10.21 (s, 1H), 8.24 (d, 1H), 7.86 (dd, 1H),7.73 (dd, 1H), 7.67-7.57 (m, 3H), 7.50 (dd, 1H); 7.45 (td, 1H), 7.35(td, 1H), 7.00 (d, 1H).

(E)-3-[3-(4-Methoxy-phenyl)-3-oxo-propenyl]-benzaldehyde

General procedure H gave the title compound as white crystals in 53%yield. ¹H NMR (CDCl₃): δ 10.08 (s, 1H), 8.42 (bs, 1H), 8.2 (m, 3H), 8.07(d, 1H), 7.88 (dt, 1H), 7.78 (d, 1H), 7.69 (t, 1H), 7.11 (d, 2H), 3.88(s, 3H).

(E)-4-[3-(2,4-Dichloro-phenyl)-acryloyl]-benzaldehyde

General procedure G gave the title compound as white crystals in 7%yield. ¹H NMR (CDCl₃): δ 10.13 (s, 1H), 8.15 (m, 3H), 8.02 (d, 2H), 7.70(d, 1H), 7.49 (d, 1H), 7.46 (d, 1H), 7.33 (dd, 1H).

(E)-3-[3-(2,4-Dichloro-phenyl)-acryloyl]-benzaldehyde

General procedure G gave the title products as a white solid in 7%yield. ¹H-NMR(CDCl₃): δ 10.12 (s, 1H), 8.5 (t, 1H), 8.32-8.26 (m, 1H),8.18 (d, 1H), 8.15-8.10 (m, 1H), 7.72 (d, 1H), 7.72 (s, 1H), 7.54-7.48(m, 2H), 7.36-7.30 (m, 1H).

Aminochalcones

A001:(E)-1-(4-Methoxy-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound asslightly yellow crystals in 16% yield. ¹H-NMR(DMSO-d₆): δ 8.15 (d, 2H),7.91 (d, 1H), 7.83 (d, 2H), 7.69 (d, 1H), 7.39 (d, 2H), 7.08 (d, 2H),6.63 (s, 2H), 3.86 (s, 3H), 3.59 (t, 4H), 3.52 (s, 2H), 2.40 (t, 4H).

A002: (E)-3-(4-Diethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure I gave fumaric acid salt of the title compound asslightly yellow crystals in 25% yield. ¹H-NMR(DMSO-d₆): δ 8.16 (d, 2H),7.92 (d, 1H), 7.84 (d, 2H), 7.69 (d, 1H), 7.43 (d, 2H), 7.09 (d, 2H),6.59 (s, 2H), 3.88 (s, 3H), 3.75 (s, 2H), 2.61 (q, 4H), 1.05 (t, 6H).

A003: (E)-1-(4-Methoxy-phenyl)-3-(4-propylaminomethyl-phenyl)-propenone

General procedure I gave fumaric acid salt of the title compound aswhite crystals in 59% yield. ¹H-NMR(DMSO-d₆): δ 8.17 (d, 2H), 7.95 (d,1H), 7.88 (d, 2H), 7.70 (d, 1H), 7.51 (d, 2H), 7.09 (d, 2H), 6.51 (s,2H), 3.96 (s, 2H), 3.87 (s, 3H), 2.70-2.61 (m, 2H), 1.60-1.49 (m, 2H),0.88 (s, 3H).

A004:(E)-3-(4-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure I gave fumaric acid salt of the title compound asoff-white crystals in 60% yield. ¹H-NMR(DMSO-d₆): δ 8.16 (d, 2H), 7.93(d, 1H), 7.83 (d, 2H), 7.70 (d, 1H), 7.41 (d, 2H), 7.09 (d, 2H), 6.59(s, 2H), 3.88 (s, 3H), 3.60 (s, 2H), 2.28 (s, 6H).

A005:(E)-3-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite crystals in 27% yield. ¹H-NMR(DMSO-d₆): δ 8.17 (d, 2H), 7.94 (d,1H), 7.86 (d, 2H), 7.70 (d, 1H), 7.48 (d, 2H), 7.09 (d, 2H), 6.53 (s,2H), 3.90 (s, 2H), 3.88 (s, 3H), 2.79 (t, 2H), 2.63 (t, 2H), 2.31 (s,6H).

A006:(E)-1-(4-Methoxy-phenyl)-3-(4-piperidin-1-ylmethyl-phenyl)-propenone

General procedure I gave the title compound as yellow crystals in 79%yield. ¹H-NMR(CDCl₃): δ 8.04 (d, 2H), 7.90 (d, 1H), 7.58 (d, 2H), 7.52(d, 1H), 7.37 (d, 2H), 6.98 (d, 2H), 3.87 (s, 3H), 3.50 (s, 2H), 2.39(br, 4H), 1.62-1.52 (m, 4H), 1.49-1.40 (m, 2H).

A007:(E)-3-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound asoff-white crystals in 23% yield. ¹H-NMR(DMSO-d₆): δ 8.17 (d, 2H), 7.94(d, 1H), 7.87 (d, 2H), 7.70 (d, 1H), 7.49 (d, 2H), 7.09 (d, 2H), 6.49(s, 2H), 3.92 (s, 2H), 3.88 (s, 3H), 2.71 (t, 2H), 2.46 (t, 2H), 2.23(s, 6H), 1.88-1.65 (m, 2H).

A008: (E)-3-(4-Dibutylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure I gave the title compound as yellow crystals in 62%yield. 1H-NMR(CDCl₃): δ 8.04 (d, 2H), 7.80 (d, 1H), 7.58 (d, 2H), 7.52(d, 1H), 7.38 (d, 2H), 6.98 (d, 2H), 3.90 (s, 3H), 3.57 (s, 2H), 2.40(t, 4H), 1.49-1.40 (m, 4H), 1.36-1.20 (m, 4H), 0.88 (t, 6H).

A009:(E)-3-{4-[(4-Diethylamino-1-methyl-butylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure I gave the title compound as brown oil in 24% yield.¹H-NMR(CDCl₃): δ 8.04 (d, 2H), 7.80 (d, 1H), 7.59 (d, 2H), 7.52 (d, 1H),7.38 (d, 2H), 6.98 (d, 2H), 3.90 (s, 3H), 3.57 (s, 2H), 2.79-2.61 (m,1H), 2.60-2.50 (q, 4H), 2.49-2.40 (t, 2H), 1.52-1.48 (m, 2H),1.38-1.23(m, 2H), 1.06 (d, 3H), 1.01 (t, 6H).

A010:(E)-3-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite crystals in 43% yield. ¹H-NMR(DMSO-d₆): δ 8.16 (d, 2H), 7.95 (s,1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.70 (d, 1H), 7.52-7.43 (m, 2H), 7.10(d, 2H), 6.58 (s, 2H), 3.95 (s, 2H), 3.88 (s, 3H), 2.85 (t, 2H), 2.70(t, 2H), 2.35 (s, 6H).

A011:(E)-3-(2,4-Dichloro-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound asoff-white crystals in 72% yield. ¹H-NMR(DMSO-d₆): δ 8.26 (d, 1H), 8.15(d, 2H), 8.04 (d, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.56 (dd, 1H), 7.52(d, 2H), 6.60 (s, 2H), 3.60 (s, 2H), 2.22 (s, 6H).

A012: (E)-1-(4-Methoxy-phenyl)-3-(3-propylaminomethyl-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite crystals in 28% yield. ¹H-NMR(DMSO-d₆): δ 8.15 (d, 2H), 7.98 (s,1H), 7.94 (d, 1H), 7.80 (d, 1H), 7.69 (d, 1H), 7.52-7.43 (m, 2H), 7.10(d, 2H), 6.52 (s, 2H), 3.99 (s, 2H), 3.86 (s, 3H), 2.69 (t, 2H),1.62-1.50 (m, 2H), 0.89 (t, 3H).

A013:(E)-1-(4-Methoxy-phenyl)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure I gave the fumaric acid salt of the title compound asoff-white crystals in 43% yield. ¹H-NMR(DMSO-d₆): δ 8.16 (d, 2H), 7.92(d, 1H), 7.80-7.75 (m, 2H), 7.69 (d, 1H), 7.45-7.37 (m, 2H), 6.99 (d,2H), 6.59 (s, 2H), 3.87 (s, 3H), 3.55 (s, 2H), 2.70-2.55 (br, 4H),2.54-2.45 (br, 4H), 2.35 (s, 3H).

A014:(E)-1-(4-Methoxy-phenyl)-3-[3-(4-methyl-[1,4]diazepan-1-ylmethyl)-phenyl]-propenone

General procedure I gave the fumaric acid salt of the title compound asoff-white crystals in 70% yield. ¹H-NMR(DMSO-d₆): δ 8.16 (d, 2H), 7.92(d, 1H), 7.80-7.75 (m, 2H), 7.70 (d, 1H), 7.45-7.40 (m, 2H), 7.09 (d,2H), 6.57 (s, 2H), 3.87 (s, 3H), 3.69 (s, 2H), 3.08-3.00 (m, 2H),2.99-2.97 (m, 2H), 2.80-2.75 (m, 2H), 2.72-2.65 (m, 2H), 2.58 (s,190-1.81 (m, 2H).

A015:(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite crystals in 23% yield. ¹H-NMR(DMSO-d₆): δ 8.16 (d, 2H), 7.92 (d,1H), 7.80-7.75 (m, 2H), 7.69 (d, 1H), 7.45-7.37 (m, 2H), 7.09 (d, 2H),6.60 (s, 2H), 3.87 (s, 3H), 3.51 (s, 2H), 2.21 (s, 6H).

A016: (E)-1-(2-Bromo-phenyl)-3-(2-dimethylaminomethyl-phenyl)-propenone

General procedure I gave the title compound as slightly green crystalsin 17% yield. ¹H-NMR(CDCl₃): δ 7.96 (d, 1H), 7.72-7.67 (m, 1H), 7.64(dd, 1H), 7.44-7.37 (m, 2H), 7.36-7.29 (m, 3H), 7.25-7.21 (m, 1H), 6.95(d, 1H), 3.35 (s, 2H), 2.07 (s, 6H).

A017:(E)-3-{3-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure I gave the title compound as yellow oil in 27% yield.¹H-NMR(CDCl₃): δ 8.06 (d, 2H), 7.80 (d, 1H), 7.65-7.50 (m, 3H),7.40-7.37 (m, 2H), 6.99 (d, 2H), 3.90 (s, 3H), 3.84 (s, 2H), 2.70 (t,2H), 2.35 (t, 2H), 2.20 (s, 6H), 1.70-1.60 (m, 2H).

A018:(E)-3-(2,5-Dimethoxy-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 64% yield. ¹H-NMR(DMSO-d₆): δ 7.99 (d, 2H), 7.90 (d,1H), 7.78 (d, 1H), 7.45-7.30 (m, 3H), 6.90 (s, 2H), 6.45 (s, 2H), 3.70(s, 2H), 3.65 (s, 3H), 3.45 (s, 3H), 2.21 (s, 6H).

A019:(E)-3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as orange oil in 24% yield.¹H-NMR(CDCl₃): δ 7.91 (d, 2H), 7.84 (d, 1H), 7.75-7.41 (m, 4H), 7.32 (d,1H), 6.62 (d, 2H), 3.58 (s, 2H), 3.32 (t, 4H), 2.26 (s, 6H), 1.64-1.54(m, 4H), 1.46-29 (m, 4H), 0.97 (t, 6H).

A020:(E)-3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite powder in 29% yield. ¹H-NMR(DMSO-d₆): δ 8.27 (d, 1H), 8.15-8.07(m, 2H), 8.02 (d, 1H), 7.95 (d, 1H), 7.77 (d, 1H), 7.65 (d, 1H),7.60-7.52 (m, 2H), 6.60 (s, 2H), 3.65 (s, 2H), 2.28 (s, 6H).

A021:(E)-3-(2,4-Dichloro-phenyl)-1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite powder in 33% yield. ¹H-NMR(DMSO-d₆): δ 8.04 (d, 1H), 7.87 (d,1H), 7.84-7.69 (m, 3H), 7.55 (d, 1H), 7.43-7.29 (m, 3H), 6.60 (s, 4H),3.61 (s, 2H), 2.70-2.55 (br, 4H), 2.50-2.40 (br, 4H), 2.35 (s, 3H).

A022:(E)-3-(2,4-Dichloro-phenyl)-1-{3-[(3-dimethylamino-propylamino)-methyl]-phenyl}-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite powder in 8% yield. ¹H-NMR(DMSO-d₆): δ 8.26-8.23 (m, 2H), 8.13 (brd, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.77 (d, 1H), 7.74 (br d, 1H),7.62-7.55 (m, 2H), 6.53 (s, 4H), 4.05 (s, 2H), 2.78 (t, 2H), 2.59 (t,2H), 2.34 (s, 6H), 1.78 (p, 2H).

A023:(E)-3-(2,5-Dimethoxy-phenyl)-1-{4-[(3-dimethylamino-propylamino)-methyl]-phenyl}-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 9% yield. ¹H-NMR(DMSO-d₆): δ 8.15 (d, 2H), 8.04 (d,1H), 7.90 (d, 1H), 7.64 (d, 2H), 7.56 (t, 1H), 7.04 (d, 2H), 6.53 (s,4H), 4.07 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.81 (t, 2H), 2.74 (t,2H), 2.45 (s, 6H), 1.86 (p, 2H).

A024:(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 60% yield. ¹H-NMR(DMSO-d₆): δ 7.84 (t, 1H),7.69 (br, 2 H), 7.65 (d, 1H), 7.49 (dd, 1H), 7.43-7.40 (m, 2H), 6.97(dd, 1H), 6.96 (t, 1H), 6.60 (s, 2H), 3.88 (s, 3H), 3.52 (s, 2H), 2.21(s, 6H).

A025:(E)-3-(4Dibutylamino-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asorange crystals in 2% yield. ¹H-NMR(DMSO-d₆): δ 8.05 (d, 2H), 7.67-7.54(m, 4H), 7.46 (d, 2H), 6.68 (d, 2H), 6.59 (s, 4H), 3.59 (s, 2H), 3.34(t, 4H), 2.71 (br, 4H), 2.41 (s, 3H,), 1.52-1.47 (m, 4H), 1.39-1.27 (m,4H), 0.92 (t, 6H).

A026:(E)-3-(2,4-Dichloro-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 50% yield. ¹H-NMR(DMSO-d₆): δ 8.06 (d, 1H), 7.71-7.70(m, 1H), 7.52-7.39 (m, 6H), 7.30 (d, 1H), 6.56 (s, 4H), 3.61 (s, 2H),2.49 (br, under DMSO, 4H), 2.35 (br, 4H), 2.27 (s, 3H).

A027:(E)-3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 31% yield. ¹H-NMR(DMSO-d₆): δ 8.10 (d, 1H), 7.71 (d,1H), 7.62-7.59 (m, 2H), 7.55-7.39 (m, 6H), 6.59 (s, 2H), 3.73 (s, 2H),2.19 (s, 6H).

A028:(E)-3-(2,5-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the title compound as brown oil in 69% yield.¹H-NMR(CDCl₃): δ 7.51 (d, 2H), 7.41-7.27 (m, 3H), 7.08-7.03 (m, 2H),6.93-6.82 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 (s, 2H), 2.38-2.19(br, 8H), 2.19 (s, 3H).

A029:(E)-3-(2,5-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as brown oil in 82% yield.¹H-NMR(CDCl₃): δ 7.58 (d, 1H), 7.43-7.32 (m, 4H), 7.13-7.07 (m, 2H),6.95-6.83 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.56 (s, 2H), 2.19 (s,6H).

A030:(E)-3-(4-Dibutylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as brown oil in 49% yield.¹H-NMR(CDCl₃): δ 7.46 (d, 1H), 7.42-7.28 (m, 5H), 7.21 (d, 1H), 6.85 (d,1H), 6.59 (d, 2H), 3.53 (s, 2 H), 3.30 (t, 4H), 2.16 (s, 6H), 1.61-1.53(m, 4H), 1.40-1.35 (m, 4H), 0.96 (t, 6H).

A031:(E)-3-(4-Dibutylamino-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the title compound as orange oil in 71% yield.¹H-NMR(CDCl₃): δ 7.38-7.28 (m, 6H), 7.18 (d, 1H), 6.82 (d, 1H), 6.59 (d,2H), 3.60 (s, 2H), 3.30 (t, 4H), 2.39-2.26 (br, 8H), 2.19 (s, 3H),1.63-1.53 (m, 4H), 1.40-1.30 (m, 4H).

A032: (E)-3-(3-Dimethylaminomethyl-phenyl)-1-pyridin-2-yl-propenone

General procedure I gave the fumaric acid salt of the title compound aswhite crystals in 30% yield. ¹H-NMR(DMSO-d₆): δ 8.82 (d, 1H), 8.28 (d,1H), 8.14-8.03 (m, 2H), 7.87 (d, 1H), 7.79-7.69 (m, 2H), 7.56-7.43 (m,2H), 7.11-7.04 (m 1H), 6.60 (s, 2H), 3.58 (s, 2H), 2.25 (s, 6H).

A033:(E)-3-(4-Dibutylamino-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as orange oil in 28% yield.¹H-NMR(CDCl₃): δ 7.98 (d, 2H), 7.79 (d, 1H), 7.53 (d, 2H), 7.44 (d, 2H),7.33 (d, 1H), 6.64 (d, 2H), 6.63 (s, 2H), 4.14 (q, 4H), 2.28 (s, 6H),1.66-1.57 (m, 4H), 1.45-1.38 (m, 4H), 0.99 (t, 6H).

A034:(E)-3-[5-(1,1-Dimethyl-allyl)-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as yellow oil in 26% yield.¹H-NMR(CDCl₃): δ 7.58 (d, 1H), 7.53 (d, 1H), 7.44-7.33 (m, 5H), 7.15 8d,1H), 6.86 (d, 1H), 6.01 (dd, 1H), 5.10-5.04 (m, 2H), 3.83 (s, 3H), 3.57(s, 2H), 2.16 (s, 6H), 1.41 (s, 6H).

A035:(E)-1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-3-(2,4-dichloro-phenyl)-propenone

General procedure F gave the title compound as orange oil in 33% yield.¹H-NMR(CDCl₃): δ 7.48-7.12 (m 8H), 6.82 (d, 1H), 3.57 (s, 2H), 1.81 (s,3H), 0.90 (s, 9H).

A036: (E)-Acetic acid1-{2-[3-(2,4-dichloro-phenyl)-acryloyl]-benzyl}-piperidin-4-yl ester

General procedure F gave the title compound as orange oil in 45% yield.¹H-NMR(CDCl₃): δ 7.60 (d, 1H), 7.48 (d, 1H), 7.45-7.29 (m, 6H), 6.97 (d,1H), 4.74-4.68 (m, 1H), 3.61 (s, 2H), 2.61-2.54 (m, 2H), 2.25-2.17 (m,2H), 2.02 (s. 3H), 1.77-1.71 (m, 2H), 1.62-1,49 (m, 2H).

A037:(E)-3-(2,4-Dichloro-phenyl)-1-(2-morpholin-4-ylmethyl-phenyl)-propenone

General procedure F gave the title compound as yellow oil in 38% yield.¹H-NMR(CDCl₃): δ 7.62 (d, 1H, 7.565 (d, 1H), 7.54-7.30 (m, 6H), 6.99 (d,1H), 3.62 (s, 2H), 3.55 (t, 4H), 2.37 (t, 4H).

A038:(E)-3-(2,4-Dichloro-phenyl)-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-propenone

General procedure F gave the title compound as orange oil in 10% yield.¹H-NMR(CDCl₃): δ 7.63 (d, 1H), 7.58 (d, 1H), 7.45-7.29 (m, 6H), 6.99 (d,1H), 3.67 (s, 2H), 2.49-2.44 (m, 2H), 2.35-2.30 (m, 2H), 2.16 (s, 6H),2.11 (s, 3H).

A039: (E)-3-(4-Diethylaminomethyl-phenyl)-1-o-tolyl-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 32% yield. ¹H-NMR(DMSO): δ 7.77 (d, 2H),7.62 (dd, 1H), 7.49-7.32 (m, 7H), 6.60 (s, 3H), 3.79 (s, 2H), 2.64 (q,4H), 2.38 (s, 3H), 1.05 (t, 6H).

A040:(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(2-methoxy-phenyl)-propenone

General procedure F gave the title compound as orange oil in 22% yield.¹H-NMR(CDCl₃): δ 7.52 (d, 1H), 7.51 (dd, 1H), 7.44-7.37 (m, 3H),7.28-7.26 (m 2H), 7.27 (d, 1H), 6.99-6.91 (m, 2H), 3,82 (s, 3H), 3.37(s, 2H), 2.18 (s, 6H).

A041: (E)-3-(4-Chloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 22% yield. ¹H-NMR(DMSO): δ 7.80 (d, 2H), 7.59 (d, 1H),7.55-7.41 (m, 5H), 7.37 (s, 2H), 6.60 (s, 2H), 3.71 (s, 2H), 2.19 (s,6H).

A042:(E)-3-(2,4-Difluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 46% yield. ¹H-NMR(DMSO): δ 8.09-8.02 (m, 1H),7.55-7.19 (m, 7H), 7.17-7.16 (m, 1H), 6.60 (s, 2H), 3.66 (s, 2H), 2.15(s, 6H).

A043:(E)-3-(3-Butylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as brown oil in 34% yield.¹H-NMR (CDCl₃): δ 7.45-7.32 (m, 4H), 7.21-7.16 (m, 1H), 7.17 (d, 1H),7.01 (d, 1H), 6.87 (d, 1H), 6.74 (t, 1H), 6.64 (dd, 1H), 3.69 (br, 1H),3.60 (s, 2H), 3.14 (t, 2H), 2.15 (s, 6H), 1.68-1.61 (m, 2H), 1.49-1.39(m, 2H), 0.98 (t, 3H).

A044:(E)-3-(4-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as brown oil in 20% yield.¹H-NMR(CDCl₃): δ 7.46 (d, 2H), 7.41-7.20 (m, 7H), 7.03 (d, 1H), 3.57 (s,2H), 3.53 (s, 2H), 2.52 (q, 4H), 2.13 (s, 6H), 1.04 (t, 6H).

A045:(E)-3-(2,4-Dichloro-phenyl)-1-(2-diethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite powder in 28% yield. ¹H-NMR (DMSO): δ 13.07 (br, 1H), 8.08 (d,1H), 7.72 (d, 1H), 7.54-7.37 (m, 6H), 7.32 (d, 1H), 6.61 (s, 2H), 3.72(s, 2H), 2.40 (q, 4H), 0.85 (t, 6H).

A046:(E)-3-(2,5-Dimethoxy-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 5% yield. ¹H-NMR (DMSO) δ 8.11 (d, 2H), 8.03 (d, 1H),7.96 (d, 1H), 7.55-7.54 (m, 1H), 7.50 (d, 2H), 7.06-7.05 (m, 2H), 6.59(s, 4H), 3.85 (s, 3H), 3.80 (s, 3H), 3.60 (s, 2H), 2.65 (br, 4H),2.56-2.49 (under DMSO, 2H), 2.37 (s, 3H).

A047:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-hydroxy-2-methoxy-5-propyl-phenyl)-propenone

General procedure F, using acidic work-up, gave the title compound asred oil in 20% yield. ¹H-NMR (DMSO) δ 10.23 (br, 1H), 7.65 (d, 1H),7.60-7.47 (m, 5H), 7.17 (d, 1H), 6.62 (s, 1H), 3.88 (s, 3H), 3.61 (s,2H), 2.59 (t, 2H), 2.18 (s, 6H), 1.73-1.63 (m, 2H), 1.01 (t, 3H).

A048:(E)-3-(2,4-Dichloro-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite powder in 27% yield. ¹H-NMR (DMSO) δ 8.08 (d, 1H), 7.72 (d, 1H),7.53-7.40 (m, 6H), 7.40 (d, 1H), 6.45 (s, 2H), 3.64 (s, 2H), 2.8 (br,4H), 2.4 (br, 4H).

A049:(E)-3-(2,5-Dimethoxy-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite powder in 30% yield. ¹H-NMR (DMSO) δ 10.37 (br, 2H), 7.53 (d, 1H),7.44-7.33 (m, 5H), 7.25 (d, 1H), 7.00 (d, 2H), 6.44 (s, 2H), 3.75 (s,3H), 3.75 (s, 3H), 3.59 (s, 2H), 2.78 (br, 4H), 2.37 (br, 4H).

A050:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-fluoro-phenyl)-propenone

General procedure F gave the title compound as brown oil in 39% yield.¹H-NMR(CDCl₃): δ 7.54-7.27 (m, 6H), 6.85 (d, 1H), 6.32 (dd, 1H), 6.18(dd, 1H), 3.47 (s, 2H), 3.18 (t, 4H), 2.08 (s, 6H), 1.61-1.49 (m, 4 H),0.87 (t, 6H).

A051:(E)-3-(2,4-Dichloro-phenyl)-1-[2-(4-hydroxy-piperidin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the title compound as brown semi-solid in 39%yield. ¹H-NMR (DMSO) δ 8.05 (d, 1H), 7.70 (d, 1H), 7.50-7.25 (m, 7H),4.46 (br, 1H), 3.55 (s, 2H), 3.35-3.32 (m, 2H), 2.47-2.44 (m, 2H (underDMSO)), 2.00-1.93 (m, 2H), 1.53-1.49 (m, 2H), 1.24-1.21 (m, 2H).

A052:(E)-1-(3-Diethylaminomethyl-phenyl)-3-(2,5-dimethoxy-phenyl)-propenone

General procedure F gave the title compound as yellow oil in 41% yield.¹H-NMR (DMSO) δ 8.07 (d, 1H), 7.95 (s, 1H), 7.87 (d, 1H), 7.59 (d, 1H),7.58 (d, 1H), 7.44 (t, 1H), 7.18 (d, 1H), 6.94 (dd, 1H), 6.88 (d, 1H),3.87 (s, 3H), 2.82 (s, 3H), 3.60 (s, 2H), 2.55 (q, 4H), 1.06 (t, 6H).

A053:(E)-3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 39% yield. ¹H-NMR (DMSO) δ 7.71-7.68 (m, 1H), 7.50 (d,1H), 7.27-7.11 (m, 7H), 6.86 (d, 1H), 6.34 (s, 4H), 3.38 (s, 2H), 3.27(s, 2H), 2.40 (t, 2H), 2.24 (t, 2H), 2.15 (s, 6H), 2.11 (br, 4H), 1.94(s, 3H), 1.79 (s, 3H).

A054:(E)-3-(2,4-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 48% yield. ¹H-NMR (DMSO) δ 7.46 (d, 1H), 7.25 (d, 1H9,7.19-7.12 (m, 5H), 6.82 (d, 1H), 6.38-6.33 (m, 2H), 6.36 (s, 4H), 3.58(s, 3H), 3.58 (s, 3H), 3.30 (s, 2H), 2.25 (br, 4H), 1.94 (s, 3H).

A055:(E)-3-(4-imidazol-1-yl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 46% yield.¹H-NMR (DMSO) δ 8.38 (t, 1H), 7.91 (d, 2H),7.85 (t, 1H), 7.74 (d, 2H), 7.44-7.31 (m, 6H), 7.14 (t, 1H), 6.60 (s,4H), 3.60 (s, 2H), 2.34 (br, 8H), 2.19 (s, 3H).

A056:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-2-yl-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 58% yield. ¹H-NMR (DMSO) δ 8.64 (d, 1H), 8.85 (td,1H), 7.76 (d, 1H), 7.48-7.37 (m, 6H), 7.19 (d, 1H), 6.68 (s, 2H), 3.55(s, 2H), 2.29 (br, 8H), 2.13 (s, 3H).

A057:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-3-yl-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 19% yield. ¹H-NMR (DMSO) δ 8.88 (d, 1H), 8.58 (dd,1H), 8.21 (d, 1H), 7.48-7.39 (m, 5H), 7.37 (d, 1H), 7.29 (d, 1H), 6.59(s, 4H), 3.60 (s, 2H), 2.41 (br, 4H), 2.33 (br, 4H), 2.21 (s, 3H).

A058:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-4-yl-propenone

General procedure F gave the fumaric acid salt of the title compound asoff-white crystals in 6% yield. ¹H-NMR (DMSO) δ 8.61 (d, 2H), 7.70 (d,2H), 7.47-7.40 (m, 5H), 7.20 (d, 1H), 6.60 (s, 4H), 3.60 (s, 2H),2.40-2.32 (br 8H), 2.21 (s, 3H).

A059:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1-methyl-1H-pyrrol-2-yl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 44% yield. ¹H-NMR (DMSO) δ 7.44-7.36 (m, 4H), 7.27(d, 1H), 7.05 (t, 1H), 6.87 (d, 1H), 6.86 (dd, 1H), 6.60 (s, 4H), 6.14(dd, 1H), 3.65 (s, 3H), 3.57 (s, 2H), 2.42-3.30 (br, 8H), 2.20 (s, 3H).

A060:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1H-pyrrol-2-yl)-propenone

General procedure F gave the fumaric acid salt of the title compound asorange crystals in 24% yield. ¹H-NMR (DMSO) δ 11.58 (1H), 7.44-7.35 (m,4H), 7.10 (d, 1H), 7.08-7.06 (m, 1H), 6.83 (d, 1H), 6.61-6.60 8m, 1H),6.59 (s, 4H), 6.19-6.17 (m, 1H), 3.55 (s, 2H), 2.47 (br, 4H), 2.35 (br,4H), 2.24 (s, 3H).

A061:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-thiophen-2-yl-propenone

General procedure F gave the oxalate salt of the title compound asslightly yellow crystals in 96% yield. ¹H-NMR (DMSO) δ 7.76 (d, 1H),7.58 (d, 1H), 7.53-7.41 (m, 6H), 7.16 (dd, 1H), 6.93 (d, 1H), 3.65 (s,2H), 3.05 (br, 4H), 2.66 (s, 3H), 2.55 (br, 4H).

A062: (E)-1,3-Bis-(2-diethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite powder in 15% yield. ¹H-NMR (DMSO) δ 13.04 (br, 2H), 7.90-7.85 (m,1H), 7.84 (d, 1H) 7.46-7.28 (m, 7H), 7.03 (d, 1H), 6.62 (s, 4H), 3.69(s, 2H), 3.47 (s, 2H), 2.43 (q, 4H), 2.29 (q, 4H), 0.87 (t, 6H), 0.76(t, 6H).

A063:(E)-3-(2,4-Dichloro-phenyl)-1-(3-diethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as orange oil in 15% yield.¹H-NMR(CDCl₃): δ 8.09 (d, 1H), 7.96 (s, 1H), 7.87 (d, 1H), 7.69 (d, 1H),7.61 (d, 1H), 7.50-7.32 (m, 3H), 7.30 (dd, 1H), 3.65 (s, 2H), 2.55 (q,4H), 1.05 (t, 6H).

A064:(E)-3-(4-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 23% yield. ¹H-NMR (DMSO) δ 7.72 (d, 2H), 7.43-7.38 (m,6H), 7.27 (d, 1H), 7.24 (d, 1H), 6.57 (s, 6H), 3.70 (s, 2H), 3.59 (s,2H), 2.36 (br, 4H), 2.32 (s, 6H), 2.26 (s, 3H).

A065:(E)-3-(3-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asoff-white crystals in 33% yield. ¹H-NMR (DMSO) δ 7.70-7.67 (m, 2H),7.50-7.40 (m, 6H), 7.25 (d, 1H), 7.21 (d, 1H), 6.56 (s, 4H), 3.67 (s,2H), 3.57 (s, 2H), 2.34 (br, 4H), 2.32 (br, 4H), 2.30 (s, 6H), 2.20 (s,3H).

A066:(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 32% yield. ¹H-NMR (DMSO) δ 7.78 (s, 1H), 7.72 (br,1H), 7.73-7.34 (m, 8H), 6.57 (s, 4H), 3.82 (s, 2H), 3.72 (s, 2H), 2.40(s, 6H), 2.21 (s, 6H).

A067:(E)-3-(2-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 54% yield. ¹H-NMR (DMSO) δ 7.91-7.87 (m, 1H), 7.87 (d,1H), 7.53-7.32 (m, 7H), 7.09 (d, 1H), 6.61 (s, 4H), 3.67 (s, 2H), 3.50(s, 2H), 2.31 (q, 4H), 2.19 (s, 6H), 0.78 (t, 6H).

A068:(E)-3-[3-(Butyl-ethyl-amino)-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as yellow oil in 3% yield.¹H-NMR (DMSO) δ 7.61-7.29 (m, 4H), 7.23-7.15 (m, 2H), 6.99 (d, 1H),6.91-6.76 (m, 2H), 6.68 (dd, 1H), 3.53 (s, 2H), 3.37 (q, 2H), 3.37 (q,2H), 2.14 (s, 6H), 1.60-1.52 (m, 2H), 1.43-1.26 (m, 2H), 1.15 (t, 3H),0.96 (t, 3H).

A069:(E)-3-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound asyellow crystals in 45% yield. ¹H-NMR (DMSO) δ 8.12 (d, 2H), 7.90 (d,1H), 7.77 (s, 1H), 7.74-7.72 (m, 1H), 7.64 (d, 1H), 7.37 (d, 2H), 7.04(d, 2H), 6.51 (s, 4H), 3.82 (s, 3H), 3.55 (s, 2H), 3.01 (t, 2H), 2.62(t, 2H), 2.57 (s, 6H), 2.13 (s, 3H).

A070:(E)-3-(2-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aspale brown crystals in 44% yield. ¹H-NMR (DMSO) δ 7.90-7.87 (m, 1H),7.61 (d, 1H), 7.44-7.36 (m, 6H), 7.26-7.24 (m, 1H), 7.00 (d, 1H), 6.57(s, 3H), 3.58 (s, 2H), 3.28 (s, 2H), 2.40 (br, 4H), 2.32 (br, 4H), 2.20(s, 3H), 1.95 (s, 6H).

A071:(E)-3-(2-Diethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 44% yield. ¹H-NMR (DMSO) δ 7.90 (dd, 1H), 7.77 (d,1H), 7.43-7.27 (m, 7H), 7.00 (d, 1H), 6.59 (s, 3H), 3.55 (s, 2H), 3.37(s, 2H), 2.30 (br, 8H), 2.27 (q, 4H), 2.19 (s, 3H), 1.09 (t, 6H).

A072: (E)-1,3-Bis-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as brown oil in 37% yield.1H-NMR(CDCl₃): δ 7.71-7.68 (m, 1H), 7.67 (d, 1H), 7.41-7.20 (m, 7H),6.93 (d, 1H), 3.57 (s, 2H), 3.29 (s, 2H), 2.11 (s, 6H), 2.03 (s, 6H).

A073:(E)-3-(4-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 39% yield. ¹H-NMR (DMSO) δ 7.73 (d, 2H), 7.55-7.42 (m,4H), 7.39 (d, 2H), 7.32 (s, 2H), 6.59 (s, 4H), 3.65 (s, 4H), 2.29 (s,6H), 2.14 (s, 6H).

A074:(E)-3-(1H-Indol-5-yl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the title compound as yellow crystals in 13%yield. ¹H-NMR (DMSO) δ 11.33 (s, 1H), 7.85 (s, 1H), 7.50 (dd, 1H),7.47-7.35 (m, 7H), 7.09 (d, 1H), 6.47 (t, 1H), 3.54 (s, 2H), 2.26 (br,4H), 2.15 (br, 4H), 2.00 (s, 3H).

A075:(E)-3-(2,4-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 32% yield. ¹H-NMR (DMSO) δ 7.75 (d, 1H), 7.63 (d,1H), 7.57-7.42 (m, 4H), 7.21 (d, 1H), 6.63-6.58 (m, 3H), 6.60 (s, 2H),3.84 (s, 3H), 3.83 (s, 3H), 3.69 (s, 2H), 2.22 (s, 6H).

A076:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-imidazol-1-yl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aspale yellow powder in 17% yield. ¹H-NMR (DMSO) δ 8.38 (t, 1H), 7.92 (d,2H), 7.85 (t, 1H), 7.74 (d, 2H), 7.56-7.43 (m, 4H), 7.38 (s, 2H), 7.13(t, 1H), 6.61 (s, 2H), 3.65 (s, 2H), 2.14 (s, 6H).

A077:(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-13-(pyridin-3-ylamino)-phenyl]-propenone

General procedure F gave the oxalate salt of the title compound asyellow crystals in 38% yield. ¹H-NMR (DMSO) δ 8.55 (br, 1H), 8.38 (d,1H), 8.06 (t, 1H), 7.54-7.13 (m, 12H), 3.67 (2H), 2.90 (br, 8H), 2.66(s, 3H).

A078:(E)-3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-i-(2,3,4-trimethoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asoff-white crystals in 14% yield. ¹H-NMR (DMSO) δ 8.00 (d, 1H), 7.83 (dd,1H), 7.44-7.31 (m, 4H), 7.24 (d, 1H), 6.93 (d, 1H), 6.59 (s, 4H), 3.87(s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.53 (s, 2H), 2.5 (br, under DMSO,4H), 2.39 (br, 4H), 2.32 (s, 3H).

A079:(E)-3-{3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-benzoicacid

General procedure F gave the title compound as brown crystals in 57%yield. ¹H-NMR (DMSO) δ 8.15 (s, 1H), 7.93 (t, 2H), 7.49 (t, 1H),7.52-7.37 (m, 4H), 7.30 (d, 1H), 7.21 (d, 1H), 3.55 (s, 2H), 2.26 (br,4H), 2.20 (br, 4H), 2.05 (s, 3H).

A080:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(2,4-dimethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 50% yield. ¹H-NMR (DMSO) δ 7.75 (d, 1H), 7.61-7.56 (m,2H), 7.50-7.45 (m, 3H), 7.19 (d, 1H), 7.22-7.07 (m, 2H), 6.59 (s, 2H),3.70 (s, 2H), 2.29 (s, 3H), 2.28 (s, 3H), 2.20 (s, 6H).

A081:(E)-3-(2,4-Dimethyl-phenyl)-1-12-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asoff-white crystals in 32% yield. ¹H-NMR (DMSO) δ 7.72 (d, 1H), 7.50 (d,1H), 7.46-7.39 (m, 4H), 7.11-7.06 (m, 3H), 6.59 (s, 4H), 3.60 (s, 2H),2.5 (under DMSO, 4H), 2.37 (br, 4H), 2.29 8s, 6H), 2.26 (s, 3H).

A082:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(1-methyl-1H-pyrrol-2-yl)-propenone

General procedure F gave the fumaric acid salt of the title compound asbrown crystals in 22% yield. ¹H-NMR (DMSO) δ 7.57-7.40 (m, 4H), 7.39 (d,1H), 7.07 (t, 1H), 6.99 (d, 1H), 6.92 (dd, 1H), 6.59 (s, 2H), 6.16 (dd,1H), 3.68 (br, 6H), 2.21 (s, 6H).

A083:(E)-3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asorange crystals in 25% yield. ¹H-NMR(DMSO-d₆): δ: 7.68 (s, 1H),7.46-7.37 (m, 5H), 7.18 (d, 1H), 7.11 (s, 1H), 6.59 (s, 4H), 6.13-6.04(dd, 1H), 5.04-5.00 (dd, 1H), 4.94-4.88 (dd, 1H), 3.83 (s, 3H), 3.56 (s,2H), 2.60-2.25 (m, 8H), 2.23 (s, 3H), 1.49 (s, 6H).

A084:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-ethoxy-phenyl)-propenone

(E)-3-(4-Dibutylamino-2-fluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone(4 mmol), was stirred in 0.1 M sodium ethanolate in EtOH (50 mL) at 25°C. overnight. The solution was evaporated on Celite® and purified byflash chromatography to give the title compound as brown oil in 0.9%yield. ¹H-NMR(CDCl₃): δ: 7.59 (d, 1H), 7.49 (d, 1H), 7.40-7.34 (m, 3H),7.29 (dd, 1H), 6.96 (d, 1H), 6.23 (dd, 1H), 6.05 (d, 1H), 4.00 (q, 2H),3.56 (s, 2H), 3.27 (t, 4H), 2.17 (s, 6H), 1.68-1.57 (m, 4H), 1.36 (t,3H), 0.94 (t, 6H).

A085:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asbrown crystals in 1% yield. ¹H-NMR(DMSO-d₆): δ 7.89-7.86 (m, 1H), 7.70(d, 1H), 7.46-7.34 (m, 6H), 7.27-7.24 (m, 1H), 7.00 (d, 1H), 6.60 (s,4H), 3.53 (s, 2H), 3.35 (s, 2H), 2.5 (under DMSO, 4H), 2.20 (br, 4H),2.20 (s, 3H), 2.08 (s, 6H).

A086:(E)-3-(3-Dimethylaminomethyl-4-methoxy-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 38% yield. ¹H-NMR(DMSO-d₆): δ 8.13 (d, 2H),7.90 (d, 1H), 7.83 (dd, 1H), 7.78 (d, 1H), 7.67 (d, 1H), 7.10 (t, 3H),6.58 (s, 2H), 3.87 (s, 6H), 3.74 (s, 2H), 2.38 (s, 6H).

A087:(E)-1-(2-Methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 3% yield. ¹H-NMR(DMSO-d₆): δ 7.92 (d, 1H),7.84-7.81 (m, 1H), 7.55-7.49 (m, 1H), 7.43 (dd, 1H), 7.38-7.28 (m, 3H),7.19 (d, 1H), 7.15 (d, 1H), 7.06 (td, 1H), 6.60 (s, 4H), 3.84 (s, 3H),3.45 (s, 2H), 2.5 (under DMSO, 4H), 2.30 (br, 4H), 2.24 (s, 3H).

A088:(E)-1-(2-Fluoro-4-methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 15% yield. ¹H-NMR(DMSO-d₆): δ 8.12 (d, 1H),7.87-7.77 (m, 2H), 7.40-7.29 (m, 4H), 7.01-6.91 (m, 2H), 6.60 (s, 3H),3.87 (s, 3H), 3.56 (s, 2H), 2.5 (under DMSO, 4H), 2.41 (br, 4H), 2.28(s, 3H).

A089:(E)-3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aspale brown crystals in 4% yield. ¹H-NMR(DMSO-d₆): δ 7.91-7.88 (m, 1H),7.75 (d, 1H), 7.50-7.33 (m, 7H), 7.13 (d, 1H), 6.57 (s, 6H), 3.62 (s,2H), 3.48 (s, 2H), 2.79 (t, 2H), 2.5 (under DMSO, 2H), 2.46 (s, 6H),2.12 s, 6H), 2.00 (s, 3H).

A090:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-3-ylamino)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 7% yield. ¹H-NMR(DMSO-d₆): δ 8.46 (s, 1H), 8.36 (d,1H), 8.06 (dd, 1H), 7.64-7.13 (m, 11H), 6.60 (s, 3H), 3.65 (s, 2H), 2.16(s, 6H).

A091:(E)-3-(2-Dimethylaminomethyl-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as brown oil in 48% yield.1H NMR (CDCl₃) δ 8.30 (d, 1H), 7.97-7.94 (m, 2H), 7.79-7.76 (m, 1H),7.58 (d, 1H), 7.50-7.45 (m, 2H, 7.38-7.35 (m, 3H), 3.55 (s, 2H), 3.53(s, 2H), 2.29 (s, 6H), 2.26 (s, 6H).

A092:(E)-1-(3-Dimethylaminomethyl-phenyl)-3-(3-morpholin-4-ylmethyl-phenyl)-propenone

General procedure F gave the title compound as yellow oil in 26% yield.¹H NMR (CDCl₃) δ 7.98-7.94 (m, 2H), 7.84 (d, 1H), 7.64-7.28 (m, 7H),3.75 (t, 4H), 3.56 (s, 2H), 3.55 (s, 2H), 2.49 (t, 4H), 2.30 (s, 6H).

A093:(E)-1-(3-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the title compound as brown oil in 18% yield.¹H NMR (DMSO) δ 8.31 (d, 1H), 7.94-7.91 (m, 2H), 7.75-7.72 (m, 1H), 7.55(d, 1H), 7.48-7.39 (m, 2H), 7.33 (dd, 3H), 7.26 (s, 2H), 3.60 (s, 2H),3.51 (s, 2H), 2.52-2.33 (bs, 4H), 2.26 (s, 6H), 2.25 (s, 3H).

A094:(E)-1-(3-Dimethylaminomethyl-phenyl)-3-(4-pyridin-2-yl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 3% yield. ¹H NMR (DMSO) δ 8.70 (d, 1H),8.21-7.98 (m, 8H), 7.92 (d, 1H), 7.81 (d, 1H), 7.66 (d, 1H), 7.57 (t,1H), 3.39 (dd, 1H), 6.60 (s, 2H), 3.74 (s, 2H), 2.32 (s, 6H).

A095:(E)-1-(4-Methoxy-phenyl)-3-(3-{[methyl-(2-methylamino-ethyl)-amino]-methyl}-phenyl)-propenone.

General procedure I gave the title compound as slightly yellow crystalsin 34% yield. ¹H-NMR (CDCl₃) δ 8.05 (d, 2H), 7.80 (d, 1H), 7.75 (s, 1H),7.61-7.57 (m, 1H), 7.56 (d, 1H), 7.48-7.37 (m, 2H), 6.98 (d, 2H), 3.89(s, 3H), 3.56-3.40 (m, 2H), 3.31 (s, 2H), 2.62-2.56 (m, 2H), 2.20 (s,9H).

A096:(E)-3-(2-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asslightly yellow crystals in 12% yield. ¹H NMR (DMSO) δ 8.10 (d, 1H),7.98-7.80 (m, 2H), 7.40-7.31 (m, 4H), 7.01-6.92 (m, 2H), 6.59 (s, 3H),3.87 (s, 3H), 3.50 (s, 2H), 2.14 (s, 6H).

A097:(E)-3-(2-Dimethylaminomethyl-phenyl)-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 17% yield. ¹H NMR (DMSO) δ 7.99 (d, 1H), 7.85-7.82 (m,1H), 7.49-7.28 (m, 5H), 6.94 (d, 1H), 6.59 (s, 4H), 3.87 (s, 3H), 3.83(s, 3H), 3.78 (s, 3H), 3.46 (s, 2H), 2.11 (s, 3H).

A098:(E)-3-(3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aspale yellow crystals in 16% yield. ¹H NMR (DMSO) δ 8.17 (d, 2H), 7.93(d, 1H), 7.84 (s, 1H), 7.78-7.76 (m, 1H), 7.70 (d, 1H), 7.42 (d, 2H),7.09 (d, 2H), 6.59 (s, 2H), 3.87 (s, 3H), 3.66 (s, 2H), 3.56 (t, 2H),2.54 (t, 2H), 2.26 (s, 3H).

A099: (E)-1-(4-Methoxy-phenyl)-3-(3-methylaminomethyl-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 18% yield. 1H NMR (DMSO) δ 8.15 (d, 2H), 8.04 (s,1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.69 (d, 1H), 7.52-7.47 (m, 2H), 7.09(d, 2H), 6.51 (s, 2H), 4.04 (s, 2H), 3.87 (s, 3H), 2.48 (s, 3H).

A100:(E)-1-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone

General procedure F gave the title compound as yellow crystals in 37%yield. ¹H-NMR (CDCl₃) δ 8.17 (d, 1H), 7.94-7.91 (m, 2H), 7.86 (d, 1H),7.67 (d, 1H), 7.63-7.57 (m, 4H), 7.55-7.43 (m, 3H), 7.35 (t, 1H), 7.03(d, 1H), 3.96 (s, 3H), 3.51 (s, 2H), 2.27 (s, 6H).

A101:(E)-3-{3-[(2-Methoxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 63% yield. ¹H NMR (DMSO) δ 8.15 (d, 2H), 7.97 (s, 1H),7.94 (d, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.49-7.45 (m, 2H), 7.10 (d,2H), 6.55 (s, 2H), 3.99 (s, 2H), 3.87 (s, 3H), 3.52 (t, 2H), 3.26 (s,3H), 2.88 (t, 2H).

A102:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2-methoxy-5-(pyridin-3-ylamino)-phenyl]-propenone

General procedure F gave the title compound as yellow crystals in 35%yield. ¹H NMR (CDCl₃) δ 8.29 (dd, 1H), 8.13 (dd, 1H), 7.56 (d, 1H),7.43-7.33 (m, 5H), 7.28-7.22 (m, 1H), 7.18-7.14 (m, 2H), 7.10 (d, 1H),6.90 (d, 1H), 5.60 (s, 1H), 3.85 (s, 3H), 3.57 (s, 2H), 2.16 (s, 6H).

A103:(E)-3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propanone

Triethylsilane (0.150 mol) was added to a solution of3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone(0.0075 mol) in trifluoro acetic acid stirred at 25° C. for 30 hours,before the solution was poured into ice-cold NaOH (2M, 150 mL).Extracted with EtOAc, dried over Na₂SO₄, filtered and evaporated onCelite®. Purified by flash chromatography (EtOAc/heptane, 3% Et₃N). Theresulting oil was dissolved in MeOH:Et₂O (1:9 v/v, 10 mL) and a solutionof fumaric acid in MeOH:Et₂O (1:9 v/v) was added. The fumaric acid saltof title compound was isolated as white crystals in 24% yield (614mg).The purity was >95% determined by HPLC. ¹H-NMR (DMSO) δ 12.96 (br,1H), 7.58-7.35 (m, 7H), 6.60 (s, 2H), 3.57 (s, 2H), 3.16 (t, 2H), 3.00(t, 2H), 2.14 (s, 6H).

A104:(E)-3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 61% yield. ¹H-NMR(DMSO-d₆) δ 7.83 (t, 1H), 7.62 (d,2H), 7.63 (d, 1H), 7.47 (dd, 1H), 7.32 (d, 2H), 7.05-6.90 (m, 2H), 6.56(s, H, fumarat), 3.87 (s, 3H), 2.90-2.68 (m, 4H), 2.39 (s, 6H).

A105:(E)-1-(4-Methoxy-phenyl)-3-(3-piperazin-1-ylmethyl-phenyl)-propenone

Prepared by general procedure I using piperazine-1-carboxylic acidtert-butyl ester followed by deprotecton using trifluoroacetic acid inmethylene chloride. The title compound was isolated as trifluoroacetatesalt 43% yield (yellow crystals). ¹H-NMR (DMSO-d₆) δ 8.16 (d, 2H), 7.95(m, 3H), 7.71 (d, 1H), 7.53 (m, 2H), 7.1 0 (d, 2H), 3.88 (s, 3H), 3.33(bs, 4H), 3.16 (bs, 4H).

A106:(E)-3-(3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone

Prepared by refuxing A101, formic acid (20 eqv) and formaldehyde (20eqv) in water for 18 hours. The fumaric acid salt of the title compoundwas isolated in 70% yield (yellow crystals). ¹H-NMR (DMSO d₆) δ 8.16 (d,2H), 7.89 (d, 1H), 7.79 (m, 2H), 7.69 (d, 1H), 7.42 (m, 2H), 7.09 (d,2H), 6.61 (s, 2H), 3.87 (s, 3H), 3.63 (s, 2H), 3.49 (t, 2H), 3.24 (s,3H), 2.61 (s, 3H), 2.24 (s, 3H).

A107:(E)-3-(3-{[(2-Amino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone

General procedure I using (2-Methylamino-ethyl)-carbamic acid tert-butylester followed by deprotection using Trifluoroacetic acid in CH₂Cl₂. Thefumaric acid salt of the title compound was isolated in 10% yield(yellow crystals). ¹H-NMR (DMSO-d₆) δ 8.17 (d, 2H), 7.95 (d, 1H),7.86-7.77 (m, 2H), 7.72 (d, 1H), 7.43-7.41 (m, 2H), 7.09 (d, 2H), 6.41(s, 2H), 3.87 (s, 3H), 3.57 (s, 2H), 2.94 (t, 2H), 2.59 (t, 2H), 2.14(s, 3H).

A108:(E)-3-{3-[(2-Hydroxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone

General procedure I gave the fumaric acid salt of the title compound asyellow crystals in 26% yield. ¹H-NMR (DMSO-d₆) δ 8.16 (d, 2H), 7.96-7.91(m, 2H), 7.76 (dt, 1H), 7.69 (d, 1H), 7.46-7.43 (m, 2H), 7.10 (d, 2H),6.49 (s, 1H), 3.91 (s, 2H), 3.87 (s, 3H), 3.55 (t, 2H), 2.72 (t, 2H).

A109:(E)-3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure F gave the title compound as yellow crystals in 18%yield. ¹H-NMR (DMSO-d₆): δ 8.15 (d, 2H), 7.86 (t, 1H), 7.78 (d, 2H),7.68 (dd,1H), 7.60-7.45 (m, 3H), 7.43-7.35 (m, 2H), 7.02-6.90 (m, 2H),3.86 (s, 3H), 3.50 (s, 2H), 2.15 (s, 6H).

A110:(E)-3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asorange crystals in 14% yield. ¹H-NMR (d₆-DMSO): δ 8.14-8.11 (m, 2H),7.65 (d, 2H), 7.64 (d, 1H), 7.56 (d, 1H), 7.15 (d, 1H), 6.68 (d, 2H),6.58 (d, 2H), 3.90 (s, 3H), 3.71 (s, 2H), 3.34 (t, 4H), 2.35 (s, 6H),1.58-1.47 (m, 4H), 1.36 (sixtet, 4H), 0.93 (s, 6H).

A1111:(E)-3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite powder in 49% yield. ¹H-NMR (d₆-DMSO): δ 8.18 (d, 2H), 8.04-7.97(m, 2H), 7.85 (d, 1H), 7.42-7.31 (m, 3H), 7.09 d, 2H), 6.56 (s, 2H),3.87 (s, 3H), 3.00 (dd, 2H) 2.64 (dd, 2H), 2.39 (s, 6H).

A112:(E)-3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asbeighe crystals in 34% yield. ¹H-NMR (d₆-DMSO): δ 7.67-7.82 (m, 3H),7.46-7.29 (m, 4H), 7.01-6.92 (m, 2H), 6.56 (s, 2H), 3.87 (s, 3H), 2.97(dd, 2H), 2.64 (dd, 2H), 2.39 (s, 6H).

A113:(E)-3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound aswhite crystals in 35% yield. ¹H-NMR (d₆-DMSO): δ 7.84-7.79 (m, 2H),7.42-7.38 (m, 2H), 7.37-7.29 (m, 3H), 6.95 (d, 1H), 6.58 (s, 3H), 3.88(s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 2.97 (dd, 2H), 2.70 (dd, 2H), 2.42(s, 6H).

A114:(E)-3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asbeighe crystals in 43% yield. ¹H-NMR (d₆-DMSO): δ 8.18 (d, 2H), 7.93 (d,1H), 7.83 (d, 2H), 7.70 (d, 1H), 7.36 (d, 2H), 7.10 (d, 2H), 6.57 (s,2H), 3.88 (s, 3H), 2.92 (bs, 4H), 2.5 (s, 6H).

A115:(E)-3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 44% yield. ¹H-NMR (d₆-DMSO): δ 7.68 (d, 2H), 7.54 (d,1H), 7.42 (d, 1H), 7.37 (d, 1H), 7.33 (d, 2H), 6.94 (d, 1H), 6.55 (s,2H), 3.88 (s, 3H), 3.84(s, 3H), 3.79 (s, 3H), 2.86 (br, 4H), 2.47 (s,6H).

A116:(E)-3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 32% yield. ¹H-NMR (d₆-DMSO): δ 8.09 (d, 2H), 8.02 (d,1H), 7.89 (d, 1H), 7.55 (bs, 1H), 7.40 (d, 2H), 7.04 (bs, 2H), 6.56 (s,2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.98-2.93 (m, 2H), 2.90-2.85 (m, 2H),2.47 (s, 6H).

A117:(E)-1-[4-(2-Dimethylamino-ethyl)-phenyl]-3-(4-methoxy-biphenyl-3-yl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 95% yield. ¹H-NMR (d₆-DMSO): δ 8.27 (d, 1H),8.14-8.01 (m, 4H), 7.78-7.75 (m, 3H), 7.51-7.44 (m, 4H), 7.36 (tt, 1H),7.22 (d, 1H), 6.57 (s, 2H), 3.95 (s, 3H), 2.96-2.90 (m, 2H), 2.85-2.79(m, 2H), 2.43 (s, 6H).

A118:(E)-3-(4,2′-Dimethoxy-biphenyl-3-yl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 27% yield. ¹H-NMR (d₆-DMSO): δ 8.12-8.06 (m, 3H),8.02 (d, 1H), 7.91 (d, 1H), 7.56 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 2H),7.14 (bt, 2H), 7.07 (td, 1H), 6.56 (s, 2H), 3.94 (s, 3H), 3.78 (s, 3H),2.97-2.92 (m, 2H), 2.89-2.84 (m, 2H), 2.47 (s, 6H).

A119:(E)-3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 50% yield. ¹H-NMR (d₆-DMSO): δ 8.07 (d, 1H), 8.02 (d,1H), 7.77-7.74 (m, 2H), 7.67 (dd, 1H), 7.51-7.36 (m, 6H), 6.95 (d, 1H),3.87 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.46 (s, 2H), 2.12 (s, 6H).

A120:(E)-3-(2,5-Dimethoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 18% yield. ¹H-NMR (d₆-DMSO): δ 8.08-8.05 (m, 2H),7.98 (d, 1H), 7.85 (d, 1H), 7.51 (bs, 1H), 7.03 (d, 2H), 6.96 (d, 1H),6.59 (s, 3H), 3.94 (bs, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.47 (s, 6H).

A121:(E)-3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 4% yield. ¹H-NMR (d₆-DMSO): δ 8.01 (dd, 1H), 7.95 (d,1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.14 (bs, 1H), 6.92 (d,1H), 6.59 (s, 2H), 6.11 (dd, 1H), 5.03 (dd, 1H), 4.93 (dd, 1H), 3.92 (s,3H), 3.84 (s, 2H), 2.39 (s, 6H), 2.08 (s, 6H).

A122:(E)-3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 41% yield. ¹H-NMR (d₆-DMSO): δ 8.22 (d, 1H),8.08-8.04 (m, 2H), 7.99 (d, 1H), 7.900 (d, 1H), 7.75 (d, 1H), 7.55 (dd,1H), 6.92 (d, 1H), 6.60 (s, 2H), 3.85 (s, 2H), 2.40 (s, 6H).

A123:(E)-3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 12% yield. ¹H-NMR (d₆-DMSO): δ 8.24 (d, 1H), 8.22(dd, 1H), 8.14 (d, 1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7.56(dd, 1H), 7.18 (d, 1H), 6.58 (s, 2H), 3.92 (s, 3H), 3.64 (s, 2H), 2.3(s, 6H).

A124:(E)-3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 40% yield. ¹H-NMR (d₆-DMSO): δ 8.14 (dd, 1H), 8.08(d, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.83 (s, 1H), 7.18 (d, 1H), 7.15(s, 1H), 6.58 (s, 2H), 6.11 (dd, 1H), 5.04 (dd, 1H), 4.93 (dd, 1H), 3.93(s, 3H), 3.91 (s, 3H), 3.69 (bs, 2H), 2.34 (s, 6H), 1.54 (s, 5 6H).

A125:(E)-3-(3′,5′-Dichloro-4,6-dimethoxy-biphenyl-3-yl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 45% yield. ¹H-NMR (d₆-DMSO): δ 8.18 (dd, 1H), 8.08(d, 1H), 8.01 (d, 1H), 7.97 (s, 1H), 7.85 (d, 1H), 7.57 (bs, 3H), 7.15(d, 1H), 6.84 (s, 1H), 6.58 (s, 2H), 401 (s, 3H), 3.92 (s, 3H), 3.91 (s,3H), 3.65 (s, 2H), 2.31 (s, 6H).

A126:(E)-1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 39% yield. ¹H-NMR (d₆-DMSO): δ 8.24-8.20 (m, 2H),8.09 (d, 1H), 8.06 (d, 1H), 8.00 (d, 1H), 7.77-7.75 (m, 3H), 7.48 (t,2H), 7.36 (tt, 1H), 7.22 (d, 1H), 7.15 (d, 1H), 6.57 (s, 1H), 3.93 (s,3H), 3.90 (s, 3H), 3.58 (s, 2H), 2.27 (s, 6H).

A127:(E)-3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 34% yield. ¹H-NMR (d₆-DMSO): δ 8.10 (d, 1H), 7.73 (d,1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.51 (dd, 1H), 7.48 (d, 1H), 7.07 (d,1H), 6.97 (d, 2H), 6.59 (s, 2H), 3.84 (s, 3H), 3.69 (s, 2H), 2.16 (s,6H).

A128:(E)-3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 29% yield. ¹H-NMR (d₆-DMSO): δ 8.02-7.98 (m, 1H),7.95 (d, 1H), 7.76 (d, 1H), 7.62 (d, 1H), 7.21 (t, 1H), 7.09 (d, 1H),6.97 (bs, 1H), 6.88 (d, 1H), 6.69 (dd, 1H), 6.58 (s, 1H), 3.77 (s, 2H),3.31 (t, 4H), 2.34 (s, 6H), 1.56-1.46 (m, 4H), 1.32 (sixtet, 4H), 0.93(t, 6H).

A129:(E)-3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 66% yield. ¹H-NMR (d₆-DMSO): δ 8.16 (dd, 1H), 8.12(d, 1H), 7.76 (d, 1H), 7.66 (d, 1H), 7.22 (t, 1H), 7.17 (d, 1H), 7.10(d, 1H), 6.98 (bs, 1H), 6.71 (dd, 1H), 6.59 (s, 2H), 3.91 (s, 3H), 3.69(s, 2H), 3.31 (t, 4H), 2.34 (s, 6H), 1.56-1.47 (m, 4H), 1.33 (sixtet,4H), 0.93 (t, 6H).

A130:(E)-1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 28% yield. ¹H-NMR (DMSO-d₆): δ 8.60 (d, 1H), 8.44(dd, 1H), 7.76 (dt, 1H), 7.64 (d, 1H), 7.34 (dd, 1H), 7.24 (s, 2H),7.14-7.07 (m, 2H), 6.98 (dd, 1H), 6.93-6.91 (m, 2H), 6.68 (dd, 1H), 6.60(s, 3H), 6.41 (bs, 1H), 4.36 (s, 2H), 3.84 (s, 3H), 3.69 (s, 2H), 2.19(s, 6H).

A131:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow crystals in 86% yield. ¹H-NMR (DMSO-d₆): δ 9.06 (s, 1H), 8.21 (d,2H), 7.53-7.35 (m, 7H), 7.30-7.23 (m, 3H), 6.94 (d, 2H), 6.60 (s, 3H),3.62 (s, 2H), 2.12 (s, 6H).

A132:(E)-1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propenone

General procedure F gave the fumaric acid salt of the title compound asyellow-brown crystals in 29% yield. ¹H-NMR (DMSO-d₆): δ 8.85 (s, 1H),8.20 (d, 2H), 7.55 (d, 1H), 7.51 (bs, 1H), 7.44-7.36 (m, 2H), 7.31 (d,2H), 7.23 (dt, 1H), 7.04 (d, 1H), 6.94-6.91 (m, 3H), 3.82 (s, 3H), 3.56(s, 2H), 2.07 (s, 6H).

A133:(E)-3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure F gave the title compound as yellow-white crystals in25% yield. 1H NMR (CDCl₃) δ 8.05 (d, 1H), 7.92 (dd, 1H), 7.78 (d, 1H),7.48 (d, 1H), 7.47 (d, 1H), 7.41 (d, 1H), 6.89 (d, 1H), 3.82 (s, 3H),3.78 (s, 3H), 2.67 (bs, 8H), 2.33 (s, 3H), 1.41 (s, 9H), 1.35 (s, 9H).

A134:(E)-3-(5-tert-Butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure F gave the title compound as orange crystals in 23%yield. ¹H NMR (CDCl₃) δ 8.04 (d, 1H), 7.92 (dd, 1H), 7.77 (d, 1H), 7.63(d, 1H), 7.61 (d, 1H), 7.39 (dd, 1H), 6.89 (dd, 1H), 3.90 (s, 3H), 3.76(s, 2H), 2.37 (s, 6H), 1.34 (s, 9H).

A135:(E)-3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure F gave the title compound as orange crystals in 21%yield. ¹H NMR (CDCl₃) δ 8.05 (d, 1H), 7.93 (dd, 1H), 7.78 (d, 1H), 7.49(d, 1H), 7.49 (d, 1H), 7.41 (d, 1H), 6.91 (d, 1H), 3.78 (s, 3H), 3.77(s, 2H), 2.39 (s, 6H), 1.42 (s, 9H), 1.35 (s, 9H).

A136:(E)-3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure E gave the title product as a red oil in 9% yield.¹H-NMR (DMSO-d₆): δ 7.48 (d, 1H), 7.46.7.42 (m, 2H), 7.38 (s, 1H),7.37-7.24 (m, 2H), 6.96 (d, 1H), 6.48 (s, 1H), 6.21 (dd, 1H), 4.95 (s,1H), 4.90 (dd, 1H), 3.73 (s, 3H), 3.45 (s, 2H), 2.04 (s, 6H).

A137:(E)-3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure E gave the title product as orange oil in 41% yield.¹H-NMR (DMSO-d₆): δ 7.93 (dt, 1H), 7.93 (d, 1H), 7.88 (br, 1H), 7.56 (d,1H), 7.54-7.47 (m, 3H), 6.53 (s, 1H), 6.24 (dd, 1H), 4.96 (dd, 1H), 4.91(dd, 1H), 3.82 (s, 3H), 3.48 (s, 2H), 2.17 (s, 6H), 1.45 (s, 6H).

A138:(E)-3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure F gave the title compound as beighe crystals in 57%yield. ¹H-NMR (DMSO): δ 8.12 (d, 1H), 7.80-7.77 (m, 2H), 7.69 (d, 1H),7.63 (d, 1H), 7.50-7.36 (m, 7H), 7.34 (d, 1H), 7.23 (d, 1H), 3.52 (s,2H), 3.31 (s, 2H), 2.02 (s, 6H), 1.98 (s, 6H).

A139:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-propenone

General procedure F gave the title compound as yellow oil in 30% yield.¹H-NMR (DMSO-d₆): δ 8.58 (d, 1H), 8.43 (dd, 1H), 7.75 (dt, 1H),7.47-7.31 (m, 5H), 7.12-7.00 (m, 3H), 6.87-6.85 (m, 2H), 6.68 (bd, 1H),6.39 (t, 1H), 4.35 (d, 2H), 3.46 (s, 2H), 2.00 (s, 6H.

Determination of Metabolic Stability

Incubations were performed with Wistar rat liver microsomes (0.25 mg/ml)in 2% sodium bicarbonate solution. NADP (0.13 mg/ml),glucose-6-phosphate (0.63 mg/ml) and glucose-6-phosophate dehydrogenase(0.38 units/ml) were used as NADPH generation system and UDPGA (0.48mg/ml) was added to include the phase II reaction, glucuronic acidconjugation, in the assay. After 5 minutes of pre-incubation thereaction was started by addition of the test article to give a finalconcentration of 20 μM. Samples were incubated for 15 min at 37° C. andthe reactions were terminated by addition of equal volumes ofacetonitrile. Blank incubations were performed at the same concentrationbut without addition of microsomes. Both blank and microsome-containingsamples were made in replicats of three. Prior to analysis samples werecentrifuged for 10 min. at 3500 rpm, HPLC system:

The fraction of compound metabolised during the 15 min of incubation wasdetermined by comparison of blank and microsome-containing samples usinga Waters Alliance 2690 separation module and Waters 996 PDA-detector(Waters. Milford, Mass., USA.) Separation was performed on a XTerra MSC₁₈ column (150*2.1 mm I.D., 3.5 μm particle size) (Waters Milford,Mass., USA) by. initial conditions were 40% mobile phase A(acetonitrile) and 60% mobile phase B (10 mM ammonium acetate pH 9.5).During the first 20 minutes, the mobile phase was changed via a lineargradient to 90% A and 10% B. This was followed by a 5 minutes lineargradient to initial conditions, which were maintained for 5 min. Theflow rate was 0.20 ml/min and injection volume 10 μl.

Determination of Solubility

Solubility of the compounds was determined by preparing a saturatedsolution of compound in 0.3 M phosphate buffer (pH 7.4±0.3) in a brownglass tube. The suspensions were rotated slowly for 24 hours. Aliquotswere centrifuged for 10 minutes at 14.000 rpm and supernatants werediluted in 40% (v/v) acetonitrile in water prior to HPLC analysis.Concentrations of analytes were quantified against a standard curve andused as term of solubility.

The HPLC-UV method used for the assessment of solubility is the same asused in the in vitro metabolism assay.

Pharmacokinetic Studies

Evaluation of the pharmacokinetic properties of the compounds was doneusing female NMRI mice (weighing app. 30 g). Test articles wereadministrated intravenously and orally as a cassette dose formulationscontaining three compounds or as individual compounds. Samples of serumwere taken at defined timepoints.

Standards and QC-samples in plasma were prepared and the serumconcentrations of the test compounds quantified by HPLC-MS.

Prior to analysis, proteins were precipitated by deluding the samples(1:1) (v/v) with 100% acetonitrile followed by centrifugation at 14.000rpm in 10 min. The supernatant was used for the analysis.

HPLC-MS System:

A Waters Alliance HPLC-system (Milford, Mass., USA) was coupled to aQuatro Micro triple quadropl mass spectrometer (Micromass, Manchester,UK) operating in positive (ESI) mode. Separation was performed on aXTerra MS C₁₈ column (150*2.1 mm I.D., 3.5 μm particle size) (WatersMilford, Mass., USA).

Mobile phase A: 0.1% (v/v) formic acid or 10 mM ammonium acetatepH-adjusted to 9.5 in MilIQ-water, mobile phase B: 100% methanol. Thegradient was as follows: 0 min=70% A-30% B, 0-10 min. a linear gradientto 10% A and 90% B this was maintained till 11 min, 11-13 lineargradient to 70% A and 30% B this was maintained till 18 min. The flowrate was 0.20 ml/min, injection volume 10 μl.

Biological Testing

General Methods

In vitro Microbiological Testing

MIC Determination in Broth Microdilution Assay

Compounds were screened for activity against a panel of 10 differentnon-fastidious bacteria growing aerobically (Staphylococcus aureusATCC29213; Staphylococcus aureus ATCC33591; Staphylococcus intermedius#2357(clinical isolate from the Copenhagen area); Enterococcus faecalisATCC29212;Enterococcus faeclum #17501 (vancomycin-resistant clinicalisolate); Streptococcus pneumoniae #998 (clinical isolate);Streptococcus pyogenes #14813 (clinical isolate); Streptococcusagalactiae #19855 (clinical isolate); Eschericia coli ATCC25922 andEscherdcia coli ESS). The screening assay was done in 200 μl MH-brothcultures in microtitre plates. For compounds exhibiting activity in theinitial screen MIC was determined in a microdilution assay usingMH-broth as described by NCLLS (National Committee for ClinicalLaboratory Standards. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standard—FifthEdition. M7-A5 NCCLS 2000) modified to include uninoculated dilutionseries of test compounds to facilitate MIC determination if the testcompound should precipitate. MIC was determined as the lowestconcentration of test compound able to inhibit visible growth ofbacteria. MICs for ATCC type strains fell within the limits posted bythe NCCLS (National Committee for Clinical Laboratory Standards.Performance Standards for Antimicrobial Susceptibility Testing; Eleventhinformational Supplement. M100-S11 NCCLS 2001) when tested againstvancomycin, tetracycline, gentamycin.

MIC and MBC Determination in Broth Macrodilution Assay

MIC and MBC of test compounds were determined in a broth macrodilutionassay using 2 ml MH-broth cultures and an inoculum of approximately5×10E5 CFU/ml as described by Amsterdam (Amsterdam, D. Susceptibilitytesting of antimicrobials in liquid media. In V. Lorian (ed.):Antibiotics in Laboratory Medicin 4. edition. Williams & Wilkins 1996).MIC was determined as the minimal concentration of test compound able toinhibit visible growth of bacteria. Samples from cultures inhibited bytest compound were plated onto unselective blood agar plates. MBC wasdetermined as the minimal concentration of test compound able todecrease colony count on these plates below 0.1% compared to theoriginal inoculum.

Killing Curve Determination

For the determination of the killing curve of a test compound a dilutionseries of test compound was made and inoculated with approximately5×10E5 CFU/ml as described for the MIC macrodilution assay above. At thetimepoints indicated 100 μl samples was withdrawn from the test tubes,serially diluted and spotted in duplicate on unselective agar plates todetermine CFU. Test compounds with bactericidal activity is capable ofdecreasing surviving colony counts (CFU/ml) when incubated withbacteria. Bactericidal activity may be either primarily dependent onconcentration of test compound or on incubation time with test compound.An example of a bactericidal compound (A031), which is primarilydependent on the concentration of the test compound is shown in FIG. 3.An example of a bactericidal compound (A019) which is primarilydependent on the incubation time with the compound is shown in FIG. 4.

MIC Determination Against Helicobacter pylon

Six strains of Helicobacter pylon were used in an agar dilution assayaccording to the standards of NCCLS (National Committee for ClinicalLaboratory Standards. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standard—FifthEdition. M7-A5 NCCLS 2000). MH-agar plates supplemented with 5% horseblood and containing a dilution series of the test compound wereinoculated in duplicate with 10 μl spots of a 2 McF suspension of thedifferent strains of H. pylori. This inoculum corresponds toapproximately 10E6 CFU/spot. Plates were then incubated in amicroaerophilic atmosphere at 35° C. for 72 hours. The MIC endpoint wasdetermined as the lowest concentration of test compound able tocompletely inhibit or most significantly reduce growth compared togrowth control plates not containing test compounds.

Activity Determination Against Anaerobic Bacteria

Screening for activity against anaerobic bacteria was done against twoisolates of Bacteroides fragilis, an isolate of Clostridium difficileand an isolate of Clostridium perfringens in an agar dilution assay asdescribed by NCCLS (National Committee for Clinical LaboratoryStandards. Methods for Antimicrobial Susceptibility Testing of AnaerobicBacteria; Approved Standard—Fifth Edition. M11-A5 NCCLS 2000) with theexception that Mueller-Hinton agar was used in place of supplementedBrucella broth. Plates containing test compound at a singleconcentration (either 100 or 150 μM) were prepared in duplicate alongwith appropriate control plates. Activity was present if growth in thepresence of test substance was absent or most significantly reducedcompared to growth control plates not containing test compound.

Leishmania promastigote Assay

A WHO reference vaccine strain of L. major originally isolated from apatient in Iran were cultured in Medium 199 with Hanks' Salts containing0.02 mg/ml gentamycin, 25 mM HEPES, 4 mM L-glutamine, and 10% heatinactivated fetal calf serum (FCS). incubation was carried out at 27° C.Promastigotes were harvested at day 3 of culture and used for the assayof inhibition of parasite growth.

The effect of test compounds on promastigotes was assessed by a methodmodified from Pearson et al. Briefly, promastigotes (0.8×10⁶/well) wereincubated in 200 μl duplicate cultures either with a dilution series oftest compound or medium alone in 96 wells flat buttom microtiter plates.After 2 h of incubation, 1.5 μCi of 3H-thymidine was added to each welland further incubated for 18 hours. The cultures were then harvested onUnifilter-GF/C microtiter filter plates (Packard instruments), washedextensively and counted in a TopCount-NXT microplate scintillationcounter (Packard instruments).

Plasmodium falciparum Assay

Plasmodium falciparum 3D7 was maintained in culture by a modification ofthe method originally described by Trager and Jensen. In brief, theparasites were grown in suspensions of human blood group 0 erythrocytes(RBC) maintained in RPMI1640 medium supplemented with 4.5 g/l Albumax II(invitrogen), 10 mM hypoxantine, 1.4 mM L-glutamine and 0.05 mg/mlgentamicin. Cultures were incubated at 37° C. in atmosphere of 92.5%nitrogen, 5.5% carbon dioxide, and 2% oxygen. To obtain synchronizedcultures og parasites erythrocytes infected with late trophozoite andschizont stages were separated from ring stages and uninfected RBC bymagnet-activated cell sorting (MACS; Miltenyi BioTec) (Staalsoe, T., H.A. Giha, D. Dodoo, T. G. Theander, and L. Hvild. 1999. Detection ofantibodies to variant antigens on Plasmodium falciparum-infectederythrocytes by flow cytometry. Cytometry 35:329-336). Because of theirhigh content of paramagnetic haemozoin, erythrocytes infected with latedevelopmental stages of malaria parasites are specifically retainedwithin the column. The column was washed with PBS supplemented with 2%foetal calf serum and then the column was removed from the magnet andthe retained late developmental stages of parasites were eluted andcultured for an additional 18 hours. At this time the culture is highlysynchronous containing more than 90% ring stages.

These synchronized cultures of ring stage parasites were used to assayfor antimalarial parasites. Briefly, cultures of ring stage parasiteswere adjusted to 1% parasitemia by addition of uninfected RBC. Then,these were incubated in 125 μl duplicate cultures containing 2.5×10⁷RBC/well with either a dilution series of test compound or with mediumalone. Plates were then incubated at 37° C. for 24 hours when cultureswere labelled by the addition 1.1 μCi 3H-phenyalanine and incubatedovernight. Then, the cultures were harvested on Unifilter-GF/Cmicrofilter plates (Packard instruments) and washed extensively withwater followed by a wash with 10% H₂O₂ to bleach hemoglobin. Filterplates were counted in a TopCount-NXT microplate scintillation counter(Packard instruments).

DHODH Assay

100 μl chalcone or 0.1 M Tris-HCl pH 8.0 is added to a well in a96-wells microtiter plate. Then 50 μl enzyme dilution is added. Themicrotiter plate is placed in the Powerwave_(x)340 and the enzymaticreactions starts when adding 100 μl assay mixture. The reaction aremeasured every 20 sec. for 10 min. The samples with chalcones arecompared with the samples with 0.1 M Tris-HCl pH 8.0 and the percentinhibition is calculated. Enzyme dilution: The solution of recombinantpurified enzyme is dissolved in 0.1 M Tris-HCl pH 8 to give an initialvelocity of 0.04-0.05 ΔA/min.

2,6-dichlorophenolindophenol (DClP)-stock solution: 40 mg DClP and 10 ml99% Ethanol are mixed for min at RT. Then 100 μl 1.0 M Tris-HCl pH 8 andmiliQ H₂O are added to a final volume of 100 ml. The A₆₀₀ of theDClP-stock solution are measured in a microtiter plate on thePowerwave_(x)340 (Bio-Tek instruments, Inc.)

Dihydroorotate dehydrogenase (DHODH)-stock solution: 25 mMdihydroorotate stock-solution is prepared by first dissolving in thesame amount of mol NaOH and then miliQ H₂O is added to the final volume.

Assay mix (10 ml solution): 600 μl of DHODH-stock solution and X ml(depending on the A₆₀₀ value of stock-solution) DClP to a final A₆₀₀=2.5are mixed. Then 0.1 M Tris-HCl pH 8.0 are added to a final volume of 10ml.

Preparation of compound solution: A 10 mM stock-solution of compound(e.g. a chalcone derivative) is made in dimethylsulfoxid (DMSO). Thecompound is then diluted in 0.1 M Tris-HCl pH 8 to the testconcentrations. The final DMSO concentration in the sample is 10%

In vivo Models

Effect of Chalcones Following Multiple intra venous Administration inPlasmodium berghei K173 infected NMRI Female Mice.

Animals in groups of 6 were inoculated intra peritoneally with 1×10⁶infected red blood cells (RBC). On day 4 after infection, when theparsitaemia was 2-5%, treatment was initiated and the animals weredosed, according to the body weight recorded, once daily for 3consecutive days (day 4-7). The doses stated were administered intravenously as solutions in a suitable vehicle. Parasitaemia, as percentageinfected blood cells, was determined by counting 500 RBCs in stained(Giemsa) blood smears, prepared from blood samples from the tail veintaken on day 4 to 9 after infection.

Effect of Chalcones Following Multiple Oral Administrations inPlasmodium berghei K173 infected NMRI Female Mice.

Animals in groups of 4 were inoculated intra peritoneally with 1×10⁶infected red blood cells (RBC). 2 hours after infection, treatment wasinitiated and the animals were dosed, according to the body weightrecorded, twice daily for 3 consecutive days (day 0-3). The doses statedwere administered orally as solutions in a suitable vehicle.Parasitaemia, as percentage infected blood cells, was determined bycounting 500 RBCs in stained (Giemsa) blood smears, prepared from bloodsamples from the tail vein taken on day 6 after infection.

Biological Results

Licochalcone A (LicA) and 4′methoxy chalcone (4′MC) described in WO93/17671 are used as reference compounds in the following discussion.

Activity Against Non-fastidious Bacteria:

Licochalcone A exhibit moderate bactericidal activity against commonpathogenic Gram-positive non-fastidious bacteria includingStaphylococcus aureus, Enterococcus faecalis, Enterococcus faecium,Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcusagalactiae. Licochalcone A maintains its activity also againstantibiotic resistant bacteria, e.g. Staphylococcus aureus ATCC33591(resistant to methicillin) and Enterococcus faecium #17051 (resistant tovancomycin). In contrast, Licochalcone A have only modest or no activityagainst the prototype pathogenic Gram-negative bacterium, Eschericiacoli. 4′MC as a representative of non-hydroxyl chalcones exhibit noantibacterial effect at all.

In comparison with Licochalcone A, aminochalcones retain the activity ofLicochalcone A against pathogenic Gram-positive bacteria includingantibiotic-resistant strains (cf. Table 1). Several aminochalconesexhibit increased potency against Gram-positive pathogens (e.g. A025,A030, A019, A033, A083). in contrast to Licochalcone A, aminochalconesexhibit activity against Eschericia coli. Thus, several aminochalcones(e.g. A030, A031, A019, A083, A084) exhibit considerable activityagainst the ESS strain of E. coli, which generally is more susceptibleto antibiotics than the type strain E. coli ATCC25922. However, severalaminochalcones (e.g. A022) exhibit similar high activity against bothGram-positive bacteria and E. coli ESS and ATTC 25922 strains. Thus,aminochalcones can be modified to permeate and inhibit Gram-negativebacteria. This indicates the potential use of aminochalcones in thetreatment of infections with Gram-negative bacteria.

In the treatment of severe infections in immunocompromised patientsbactericidal action of a antibiotic is a necessity. As exemplified inFIGS. 3 and 4, aminochalcones retain the bactericidal action ofLicochalcone A. For some aminochalcones the bactericidal action ispredominantly dependent on the concentration of the compound (e.g. A031;cf. FIG. 3); for others the bactericidal action is predominantlydependent on the time of incubation with the compound (e.g. A019; cf.FIG. 4). This knowledge is helpful when designing dosing regimens for invivo efficacy trials. TABEL 1 Comparasion of the effect ofamino-chalcones and Licochalcone/4′MC on bacteria; MIC values in μM. A BC D E F G H LICA 37.5 37.5 37.5 37.5 37.5 75.0 300.0 4′-MC NA NA NA NANA NA NA NA A025 9.4 9.4 9.4 9.4 9.4 37.5 75.0 A030 9.4 9.4 9.4 18.818.8 18.8 18.8 A019 9.4 9.4 9.4 9.4 9.4 18.8 18.8 A033 4.7 9.4 4.7 9.49.4 75.0 150.0 A083 9.4 9.4 18.8 18.8 9.4 18.8 9.4 A022 37.5 37.5 37.518.8 18.8 18.8 18.8 18.8 A117 9.4 9.4 9.4 37.5 37.5 37.5 150 9.4 A1374.7 9.4 9.4 9.4 9.4 37.5 A129 4.7 9.4 9.4 9.4 9.4 37.5 9.4A: Staphylococcus aureusATCC29213;B: Staphylococcus aureus ATCC33591 (resistant to methicillin);C: Staphylococcus intermedius #2357 (clinical isolate from theCopenhagen area);D: Enterococcus faecalisATCC29212;E: Enterococcus faecium #17501 (vancomycin-resistant clinical isolate);F: Streptococcus pneumoniae#998 (clinical isolate);G: Eschericia coliATCC25922 andH: Eschericia coli ESS.NA: no activity.

Activity against Helicobacter pylori:

Colonization of the gastric mucosa with Helicobacter pylori is animportant pathogenic determinant for the development of gastritis andpeptic ulcer. Aminochalcones exhibit activity against Helicobacterpylori. Several aminochalcones (e.g. A026, A035, A037, A038, A045, A051,A063, A118, A124) exhibit MICs in the range between 12.5 μM and 100 μMwhen tested against a panel of six strains Helicobacter pylori, thatincludes strains resistant to metronidazole. Metronidazol is anantibiotic commonly included in treatment regimens designed to eradicateHelicobacter colonization for the treatment of peptic ulcer. Theactivity of aminochalcones against both metronidazole-resistant andsensitive Helicobacter pylori clearly indicates the potential use ofthese compounds in the treatment of Helicobacter infections.

Activity Against Anaerobic Bacteria:

Aminochalcones have been assayed in a single concentration of compound(100 μM) for activity against a panel of anaerobic bacteria containingcommon human pathogenic bacteria (Bacteroides fragilis, Clostridiumperfringens, Clostridium difficele). Several aminochalcones (e.g. A011,A026, A034, A037, A038, A063, A090) exhibit activity against allmicroorganisms within the test panel. This clearly indicates thepotential use of aminochalcones in treatment of infection caused byanaerobic bacteria.

Activity Against Protozoa:

Activity against Plasmodium falciparum:

Plasmodium falciparum is a protozoan parasite transmitted by themosquito, Anopheles, and causing malignant or severe malaria in humans.Licochalcone A exhibit activity against Plasmodium falciparum in vitroand protects mice from infection with P. yoelii and P. berghei (Chen etal., 1994). Aminochalcones exhibit activity in vitro against Plasmodiumfalciparum and several aminochalcones exhibit improved potency comparedto Licochalcone A (cf. Table 2 and FIG. 5). Futhermore the compounds arepotent against chloroquine resistant parasites as shown in Table 3. Theresults clearly indicate the potential use of aminochalcones in thetreatment of malaria. TABLE 2 Activity against Plasmodium falciparum3D7. Comp. LicA 4′MC A027 A035 A038 A043 A066 A090 A102 IC₅₀ (μM) 6.440.0 0.7 0.9 1.2 1.3 0.9 1.0 0.5 Comp. A127 A130 A131 A132 A139 A141IC₅₀ (μM) 0.6 0.5 0.5 0.6 0.4 0.7

TABLE 3 Activity against resistant strains of Plasmodium falciparumPlasmodium falciparum IC₅₀ (μM) 3D7(Cq-sen) DD2 (Cq-res) 7G8(Cq-res)K1(Cq-res) A027 0.7 1.1 1.1 1.1 A102 0.5 1.2 1.1 1.1 Chloroquine 0.131.0 1.09 >1.56

Activity Against Leishamania major:

Leishamania major is a protozoan parasite transmitted by the sandfly,Phlebotomus, and causing cutaneous leishmaniasis or kala-azar in humans.Licochalcone A exhibit activity against Leishmania parasites and hasshown efficacy in experimental animal models of cutaneous and visceralLeishmania infection (Chen et al., 1994). Aminochalcones exhibitactivity in vitro against Leishamania major with significantly improvedpotency compared to Licochalcone A and 4′MC (cf. Table 4 and FIG. 6).The results clearly indicate the potential use of aminochalcones in thetreatment of Leishamania infection. TABLE 4 Effect of amino-chalcones onL. major. Comp. LicA 4′MC A027 A034 A035 A037 A038 A051 A063 A083 A100IC₅₀ (μM) 4.6 5.6 0.2 0.9 0.3 0.1 0.8 0.5 0.9 1.0 0.2

Inhibition of DHODH.

Several of the amino-chalcones prepared are potent inhibitors of DHODH.The compounds are as potent as LicA and by far more potent than ordinarychalcones exemplified by 4′MC. TABLE 5 Inhibition of DHODH. Comp. LicA4′MC A020 A021 A022 A025 A035 A038 A045 Inhibition 25% 7% 23% 27% 28%26% 26% 22% 20%

Metabolism

The usefulness of chalcones as drug candidates have been limited by themetabolism of the compounds resulting in short half-lives in vivo (Lica:100% turn-over in vitro and t½=10 min in vivo).

The introduction of an amino group in the chalcone changes the metabolicproperties; this is clear from Table 6 where the metabolic turn-over ofa number of amino-chalcones are compared to LicA. The amino-chalconesprepared are expected to show low or no metabolism in vivo as themetabolic turn-over are between 0-10% (compared to 100% turn-over forLica). Consequently, the half-life of an amino-chalcone will be longer,reducing the dose needed for treatment. TABLE 6 Metabolic turn-over(rat) in vitro (%). Comp. LicA A010 A019 A029 A049 A099 A102 A110Turn-over 100% 1% 5% 3% 0% 7% 2% 6%

Solubility

The aqueous solubility of the neutral chalcones described in WO 93/17671is very low. A representative chalcone 4′-methoxy-chalcone has asolubility of <<0.05 mg/ml. A few chalcones have a higher solubility dueto (metabolically unstable) hydroxyl groups in the molecule. LicA has asolubility of approximately 0.01 mg/ml.

The amino-chalcones described in this application are by far superiorhaving solubility numbers in mg/ml (cf. Table 7). TABLE 7 Solubility inaqueous buffer at pH 7.4. Comp. A005 A010 A013 A049 A066 A069 A086Solubility >6 33.4 31.2 6.3 7.4 >10 8.9 (mg/ml)

The high solubility means that dissolution and hence absorption will beno problem. This will inevitably cause a dramatic reducing of the doseneeded making the amino-chalcones very usable as drug candidates.

Bioavailabiblity

The bioavailability of the amino chalcones in mice is in general veryhigh (e.g. 34% for A048). As the mouse is a very fast metabolizer of theamino chalcones compared to rat and human (e.g. A102 mice: 28%; rat: 2%;human: in general lower than rat) the bloavailability in rat and man isexpected to be even higher due to limited first pass metabolism.

In vivo Results

A number of amino-chalcones have significant effect in the in vivomodels. As illiustrated on FIG. 7 and 8 the compounds cause asignificant reduction of parasitaemia in plasmodium infedted mice,showing the potential of the compounds as drug candidates.

Conclusion: The use of chalcones as drug candidates for the treatment ofparasitic or bacterial infections have been limited by the low in vivopotency of the compounds and a narrow spectrum of activity.

Several factors contribute to the low in vivo potency: Fast metabolismresulting in short half-lives in vivo; Low/no solubility in theintestine and consequently low/no absorption; Medium potency of thecompounds against parasites and no activity against bacteria (except forLicA).

The amino-chalcones in this application are expected to fulfill thecriteria for a drug candidate. The metabolism is low, the solubility ishigh and the compounds are potent against parasites as well as(resistant) Gram positive and Gram negative bacteria.

1. A compound of the formula(Y¹)_(m)—Ar¹(X¹)—C(═O)VAr²(X²)—(Y²)_(p) and salts thereof; wherein Ar¹and Ar² independently are selected from aryl and heteroaryl; Vdesignates —CH₂—CH₂—, —CH═CH— or —C≡C—; m is a whole number selectedfrom the group consisting of 0, 1, and 2, p is a whole number selectedfrom the group consisting of 0, 1, and 2, wherein the sum of m and p isat least 1; each Y¹ is independently selected from an amino-functionalsubstituent of the formula-Z-N(R¹)R², each Y² is independently selected from an amino-functionalsubstituent of the formula-Z-N(R¹)R², wherein Z is a biradical —(C(R^(H))₂)_(n)—, wherein n is aninteger in the range of 1-6, and each R^(H) is independently selectedfrom hydrogen and C₁₋₆-alkyl, or wherein (R^(H))₂ is ═O; R¹ and R²independently are selected from hydrogen, optionally substitutedC₁₋₁₂-alkyl, optionally substituted C₂₋₁₂-alkenyl, optionallysubstituted C₄₋₁₂-alkadienyl, optionally substituted C₆₋₁₂-alkatrienyl,optionally substituted C₂₋₁₂-alkynyl, optionally substitutedC₁₋₁₂-alkoxycarbonyl, optionally substituted C₁₋₁₂-alkylcarbonyl,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted arylcarbonyl, optionally substituted heteroaryl,optionally substituted heteroaryloxycarbonyl, optionally substitutedheteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbon-yl; or wherein N(R¹)R²) formsan optionally substituted nitrogen-containing heterocyclic ring; X¹ andX² independently designates a substituent present 0-5 times, on Ar¹ andAr², respectively, wherein each X¹ and X² is independently selected fromthe group consisting of optionally substituted C₁₋₁₂-alkyl, optionallysubstituted C₂₋₁₂-alkenyl, optionally substituted C₄₋₁₂-alkadienyl,optionally substituted C₆₋₁₂-alkatrienyl, optionally substitutedC₂₋₁₂-alkynyl, hydroxy, optionally substituted C₁₋₁₂-alkoxy, optionallysubstituted C₂₋₁₂-alkenyloxy, carboxy, optionally substitutedC₁₋₁₂-alkoxycarbonyl, optionally substituted C₁₋₁₂-alkylcarbonyl,formyl, C₁₋₆-alkylsulphonylamino, optionally substituted aryl,optionally substituted aryloxycarbonyl, optionally substituted aryloxy,optionally substituted arylcarbonyl, optionally substituted arylamino,arylsulphonylamino, optionally substituted heteroaryl, optionallysubstituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy,optionally substituted heteroarylcarbonyl, optionally substitutedheteroarylamino, optionally substituted (heteroarylalkyl)amino,optionally substituted (heteroarylalkyl)alkylamino,heteroarylsulphonylamino, optionally substitutedheterocyclyloxycarbonyl, optionally substituted heterocyclyloxy,optionally substituted heterocyclylcarbonyl, optionally substitutedheterocyclylamino, heterocyclylsulphonylamino, amino, mono- anddi(C₁₋₆-alkyl)amino, carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, C₁₋₆-alkylsulphonyl-oxy, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, and halogen, where any nitrogen-bound C₁₋₆-alkyl isoptionally substituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,carboxy, halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, orguanidine. 2-50. (canceled)
 51. A compound of the formula(Y¹)_(m)—Ar¹(X¹)—C(═O)VAr²(X²)—(Y²)_(p) and salts thereof; wherein Ar¹and Ar² independently are selected from aryl and heteroaryl; Vdesignates —CH₂—CH₂—, —CH═CH— or —C≡C—; m is a whole number selectedfrom the group consisting of 0, 1, and 2, p is a whole number selectedfrom the group consisting of 0, 1, and 2, wherein the sum of m and p isat least 1; each Y¹ is independently selected from an amino-functionalsubstituent of the formula-Z-N(R¹)R², each Y² is independently selected from an amino-functionalsubstituent of the formula-Z-N(R¹)R², wherein Z is a biradical —(C(R^(H))₂)_(n)—, wherein n is aninteger in the range of 1-6, and each R^(H) is independently selectedfrom hydrogen and C₁₋₆-alkyl, or wherein (R^(H))₂ is ═O; R¹ and R²independently are selected from the group consisting of hydrogen,optionally substituted C₁₋₁₂-alkyl, optionally substitutedC₂₋₁₂-alkenyl, optionally substituted C₄₋₁₂-alkadienyl, optionallysubstituted C₆₋₁₂-alkatrienyl, optionally substituted C₂₋₁₂-alkynyl,optionally substituted C₁₋₁₂-alkoxycarbonyl, optionally substitutedC₁₋₁₂-alkylcarbonyl, optionally substituted aryl, optionally substitutedaryloxycarbonyl, optionally substituted arylcarbonyl, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy-carbonyl,optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl; or wherein N(R¹)R²) formsan optionally substituted nitrogen-containing heterocyclic ring; X¹ andX² independently designates a substituent present 0-5 times, on Ar¹ andAr², respectively, wherein each X¹ and X² is independently selected fromthe group consisting of optionally substituted C₁₋₁₂-alkyl, optionallysubstituted C₂₋₁₂-alkenyl, optionally substituted C₄₋₁₂-alkadienyl,optionally substituted C₆₋₁₂-alkatrienyl, optionally substitutedC₂₋₁₂-alkynyl, hydroxy, optionally substituted C₁₋₁₂-alkoxy, optionallysubstituted C₂₋₁₂-alkenyloxy, carboxy, optionally substitutedC₁₋₁₂-alkoxycarbonyl, optionally substituted C₁₋₁₂-alkylcarbonyl,formyl, C₁₋₆-alkylsulphonylamino, optionally substituted aryl,optionally substituted aryloxycarbonyl, optionally substituted aryloxy,optionally substituted arylcarbonyl, optionally substituted arylamino,arylsulphonylamino, optionally substituted heteroaryl, optionallysubstituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy,optionally substituted heteroarylcarbonyl, optionally substitutedheteroarylamino, optionally substituted (heteroarylalkyl)amino,optionally substituted (heteroarylalkyl)alkylamino,heteroarylsulphonylamino, optionally substitutedheterocyclyloxycarbonyl, optionally substituted heterocyclyloxy,optionally substituted heterocyclylcarbonyl, optionally substitutedheterocyclylamino, heterocyclylsulphonylamino, amino, mono- anddi(C₁₋₆-alkyl)amino, carbamoyl, mono- and anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, C₁₋₆-alkylsulphonyl-oxy, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, and halogen, where any nitrogen-bound C₁₋₆-alkyl isoptionally substituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,carboxy, halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, orguanidine.
 52. The compound of claim 51, wherein, when Ar¹ and Ar² areboth phenyl, V is —CH═CH—, Z is CH₂, R¹ and R² are methyl or togetherform a morpholino group, and one of m and p is 2 while the other of mand p is 0, then X¹ and X² independently designates 0-5 substituents,where such optional substituents independently are selected from thegroup consisting of optionally substituted C₁₋₁₂-alkyl, optionallysubstituted C₂₋₁₂-alkenyl, optionally substituted C₄₋₁₂-alkadienyl,optionally substituted C₆₋₁₂-alkatrienyl, optionally substitutedC₂₋₁₂-alkynyl, 2-, 3-, 5-, or 6-hydroxy, optionally substitutedC₁₋₁₂-alkoxy, optionally substituted C₂₋₁₂-alkenyloxy, carboxy,optionally substituted C₁₋₁₂-alkoxycarbonyl, optionally substitutedC₁₋₁₂-alkylcarbonyl, formyl, C₁₋₆-alkylsulphonylamino, optionallysubstituted aryl, optionally substituted aryloxycarbonyl, optionallysubstituted aryloxy, optionally substituted arylcarbonyl, optionallysubstituted arylamino, arylsulphonylamino, optionally substitutedheteroaryl, optionally substituted heteroaryloxycarbonyl, optionallysubstituted heteroaryloxy, optionally substituted heteroarylcarbonyl,optionally substituted heteroarylamino, optionally substituted(heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionallysubstituted heterocyclyloxycarbonyl, optionally substitutedheterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionallysubstituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, C₁₋₆-alkylsulphonyl-oxy, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, and halogen, where any nitrogen-bound C₁₋₆-alkyl may besubstituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, carboxy,halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidine;provided that when Ar¹ and Ar² are both phenyl, V is —CH═CH—, m is 1, pis 0, Y¹ is 2—CH₂NMe₂, X² is absent, and X¹ is present 1 time, then X¹is not 4-methoxy, when Ar¹ and Ar² are both phenyl, V is —CH═CH—, m is1, p is 0, Y¹ is 3- or 4-CH₂NR¹ R², wherein R¹ and R² are selected fromhydrogen, methyl, and ethyl, and X² is present 0 or 1 time and isselected from 4-hydroxy or 4-alkoxy, and X² is present 0 or 1 time, thenX² is not selected from the group consisting of nitro, dichloro,carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy,2-carboxyethyl, when Ar¹ and Ar² are both phenyl, V is —CH═CH—, m is 0,p is 1, Y² present 1 time and is 2- or 3CH₂NR¹R², wherein R¹ and R² areselected from hydrogen, methyl, and ethyl, X² is present 0 or 1 time andis 4-OH, and X¹ is present 0 or 1 time, then X¹ is notethoxycarbonylmethoxy or dichloro.
 53. The compound of claim 51, whereinR¹ and R² independently are selected from the group consisting ofhydrogen, optionally substituted C₁₋₁₂-alkyl, optionally substitutedC₂₋₁₂-alkenyl, optionally substituted C₂₋₁₂-alkynyl, optionallysubstituted C₁₋₁₂-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,aminocarbonyl, mono- and di(C₁₋₆-alkyl)-aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, and mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl.
 54. The compound of claim51, wherein X¹ and X² independently designates 0-4 substituents, wheresuch optional substituents independently are selected from the groupconsisting of optionally substituted C₁₋₁₂-alkyl, hydroxy, optionallysubstituted C₁₋₁₂-alkoxy, optionally substituted C₂₋₁₂-alkenyloxy,carboxy, optionally substituted C₁₋₁₂-alkylcarbonyl, formyl,C₁₋₆-alkylsulphonylamino, optionally substituted aryl, optionallysubstituted aryloxycarbonyl, optionally substituted aryloxy, optionallysubstituted arylcarbonyl, optionally substituted arylamino,arylsulphonylamino, optionally substituted heteroaryl, optionallysubstituted heteroarylamino, optionally substituted(heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, amino, mono- and di(C₁₋₆-alkyl)amino,optionally substituted heteroarylcarbonyl, optionally substitutedheteroaryloxy, heteroarylsulphonylamino, optionally substitutedheterocyclyloxy, optionally substituted heterocyclylamino, carbamoyl,mono- and di(C₁₋₆-alkyl)amino-carbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, guanidino,carbamido, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,C₁₋₆-alkylsulphonyloxy, optionally substituted C₁₋₆-alkylthio,aminosulfonyl, mono- and di(C₁₋₆-alkyl)aminosulfonyl, and halogen, whereany nitrogen-bound C₁₋₆-alkyl may be substituted with at least onesubstituent selected from the group consisting of hydroxy, C₁₋₆-alkoxy,and halogen.
 55. The compound of claim 51, wherein R¹ and R²independently are selected from the group consisting of hydrogen,optionally substituted C₁₋₆-alkyl, optionally substitutedC₁₋₆-alkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl.
 56. The compound of claim51, wherein X¹ and X² independently designates 0-3 substituents, wheresuch optional substituents independently are selected from the groupconsisting of optionally substituted C₁₋₆-alkyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy, carboxy, optionally substitutedC₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulphonylamino, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylamino,amino, mono- and di(C₁₋₆-alkyl)amino, arylsulphonylamino, optionallysubstituted heteroaryl, optionally substituted heteroarylamino,optionally substituted (heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, carbamoyl,C₁₋₆-alkylcarbonylamino, guanidino, carbamido, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyloxy, optionallysubstituted heterocyclylamino and halogen, where any nitrogen-boundC₁₋₆-alkyl may be substituted with at least one substituent selectedfrom the group consisting of hydroxy, C₁₋₆-alkoxy, and halogen.
 57. Thecompound of claim 51, wherein V designates —CH═CH—.
 58. The compound ofclaim 51, wherein at least one of Ar¹ and Ar² are aryl.
 59. The compoundof claim 58, wherein both of Ar¹ and Ar² are phenyl rings, m is 1 or 2,and p is
 0. 60. The compound of claim 51, wherein X² represents at leastone substituent selected from the group consisting of C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-alkylcarbonyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted arylamino, amino, mono- anddi(C₁₋₆-alkyl)amino, optionally substituted heteroaryl, optionallysubstituted heteroarylamino, optionally substituted(heteroarylalkyl)amino, optionally substituted(heteroarylalkyl)alkylamino, optionally substituted C₁₋₆-alkylthio,optionally substituted heterocyclyloxy, optionally substitutedheterocyclylamino and halogen.
 61. The compound of claim 51, wherein atleast one of Ar¹ and Ar² is selected from the group consisting ofthiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, thienyl, quinolyl, isoquinolyl, and indolyl. 62.The compound of claim 51, wherein Z is —(CH₂)_(n)— wherein n is 1-4. 63.The compound of claim 51, wherein one of Y¹ and Y² represents asubstituent of the formula—CH₂—N(R¹)R² wherein R¹ and R² are selected from hydrogen andC₁₋₆-alkyl.
 64. The compound of claim 63, wherein V is —CH═CH—, and Ar¹and Ar² both are phenyl rings.
 65. The compound of claim 63, wherein Y¹represents the substituent of the formula —CH₂—N(R¹)R².
 66. The compoundof claim 51, selected from the group consisting of:1-(4-Methoxy-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-propenone,3-(4-Diethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-(4-propylaminomethyl-phenyl)-propenone,3-(4-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,3-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-(4-piperidin-1-ylmethyl-phenyl)-propenone,3-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,3-(4-Dibutylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,3-{4-[(4-Diethylamino-1-methyl-butylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,3-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-(3-propylaminomethyl-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-(4-Methoxy-phenyl)-3-[3-(4-methyl-[1,4]diazepan-1-ylmethyl)-phenyl]-propenone,3-(3-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,1-(2-Bromo-phenyl)-3-(2-dimethylaminomethyl-phenyl)-propenone,3-{3-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,3-(2,5-Dimethoxy-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2,4-Dichloro-phenyl)-1-{3-[(3-dimethylamino-propylamino)-methyl]-phenyl}-propenone,3-(2,5-Dimethoxy-phenyl)-1-{4-[(3-dimethylamino-propylamino)-methyl]-phenyl}-propenone,3-(3-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,3-(4-Dibutylamino-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2,4-Dichloro-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(2,5-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2,5-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(4-Dibutylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(4-Dibutylamino-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(3-Dimethylaminomethyl-phenyl)-1-pyridin-2-yl-propenone,3-(4-Dibutylamino-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,3-[5-(1,1-Dimethyl-allyl)-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-3-(2,4-dichloro-phenyl)-propenone,Acetic acid1-{2-[3-(2,4-dichloro-phenyl)-acryloyl]-benzyl}-piperidin-4-yl ester,3-(2,4-Dichloro-phenyl)-1-(2-morpholin-4-ylmethyl-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-propenone,3-(4-Diethylaminomethyl-phenyl)-1-o-tolyl-propenone,3-(3-Dimethylaminomethyl-phenyl)-1-(2-methoxy-phenyl)-propenone,3-(4-Chloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(2,4-Difluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(3-Butylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(4-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(2-diethylaminomethyl-phenyl)-propenone,3-(2,5-Dimethoxy-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-(4-hydroxy-2-methoxy-5-propyl-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone,3-(2,5-Dimethoxy-phenyl)-1-(2-piperazin-1-yl methyl-phenyl)-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-fluoro-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-[2-(4-hydroxy-piperidin-1-ylmethyl)-phenyl]-propenone,1-(3-Diethylaminomethyl-phenyl)-3-(2,5-dimethoxy-phenyl)-propenone,3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2,4-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(4-lmidazol-1-yl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-2-yl-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-3-yl-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-4-yl-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1-methyl-1H-pyrrol-2-yl)-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1H-pyrrol-2-yl)-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-thiophen-2-yl-propenone,1,3-Bis-(2-diethylaminomethyl-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(3-diethylaminomethyl-phenyl)-propenone,3-(4-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(3-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(3-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(2-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-[3-(Butyl-ethyl-amino)-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone,3-(2-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2-Diethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1,3-Bis-(2-dimethylaminomethyl-phenyl)-propenone,3-(4-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,3-(1H-Indol-5-yl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2,4-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-(4-imidazol-1-yl-phenyl)-propenone,1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-[3-(pyridin-3-ylamino)-phenyl]-propenone,3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,3-{3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-benzoicacid,1-(2-Dimethylaminomethyl-phenyl)-3-(2,4-dimethyl-phenyl)-propenone,3-(2,4-Dimethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-(1-methyl-1H-pyrrol-2-yl)-propenone,3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-ethoxy-phenyl)-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(3-Dimethylaminomethyl-4-methoxy-phenyl)-1-(4-methoxy-phenyl)-propenone,1-(2-Methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-(2-Fluoro-4-methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-3-ylamino)-phenyl]-propenone,3-(2-Dimethylaminomethyl-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,1-(3-Dimethylaminomethyl-phenyl)-3-(3-morpholin-4-ylmethyl-phenyl)-propenone,1-(3-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,1-(3-Dimethylaminomethyl-phenyl)-3-(4-pyridin-2-yl-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-(3-{[methyl-(2-methylamino-ethyl)-amino]-methyl-phenyl)-propenone,3-(2-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,3-(2-Dimethylaminomethyl-phenyl)-1-(2,3,4-trimethoxy-phenyl)-propenone,3-(3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-(3-methylaminomethyl-phenyl)-propenone,1-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone,3-{3-[(2-Methoxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-[2-methoxy-5-(pyridin-3-ylamino)-phenyl]-propenone,3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propanone,3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,1-(4-Methoxy-phenyl)-3-(3-piperazin-1-ylmethyl-phenyl)-propenone,3-(3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phenyl)-propenone,3-(3-{[(2-3-{3-[(2-Hydroxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propenone,3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone,1-[4-(2-Dimethylamino-ethyl)-phenyl]-3-(4-methoxy-biphenyl-3-yl)-propenone,3-(4,2′-Dimethoxy-biphenyl-3-yl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone,3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2,3,4-trimethoxy-phenyl)-propenone,3-(2,5-Dimethoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,3-(3′,5′-Dichloro-4,6-dimethoxy-biphenyl-3-yl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone,3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-4-methoxy-phenyl)-propenone,3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-propenone,1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propenone,1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propenone,3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,3-(5-tert-Butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(3-dimethylaminomethyl-phenyl)-propenone,and salts thereof.
 67. A composition comprising the compound of claim 51and a pharmaceutically acceptable carrier.
 68. A method for treatingbacterial infections in a mammal comprising administering to the mammalof a compound of claim 51 and a pharmaceutically acceptable carrier. 69.A method for treatment of infections associated with protozoa in amammal comprising administering to the mammal a compound of claim 51.